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.

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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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The dona phase 2 result always had seemed "off" to me. As seen a few posts up, the CDR-sb result for the phase 2 was reported as -0.36. Yet, with the endless regressions that have been done on this thread, the result should have been closer to ~-0.46. The above result shows how things are now aligned. The black vertical line (to the lower left near the pink line) where it intersects the pink line is where the dona result should be expected on the regression given the adjustment to week 60 (Here week 60 is expected to be more comparable to the Aducanumab week 78). The intersection of the horizontal black line and the vertical black line (see the red dot) just below the pink line is the calculated dona result adjusted to week 60. There is now only a 0.01 CDR-sb deviation from where the dona result was expected to be and where it actually was (instead of the ~0.11 from the as stated results).

I will have to check to see whether the Ban2401 (Lecanemab) results need to be adjusted for a fast titration as well.
The slope now for the dona result is now 1.305. Perhaps the entire regression should now rotate downwards somewhat, this would then bring the 302 high dose and Ban2401 high in better alignment.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I know I know J11 what is this all about?

My ongoing perception is that the p-value approach really is not that helpful.
With p-values everyone endlessly repeats that the 301 and 302 low dose arms did not reach statistical significance.
Yet, in order for the results to have achieved significance they would have needed to be ~ -0.35 in the above figure which is to say way way off of the regression line. That would not make any sense. As can be seen in the regression, the 301 and 302 low doses are almost exactly on top of the regression! The odd idea is that being exactly where they should be is somehow supposed to be a sign that the trials were not successful. From the amyloid--> cognition perspective, the low dose adds strong confirmatory support for the relationship because it is where it should be.

As well as the dose effect there is also the different anti-amyloids. All of the modern anti-amyloids should also be very close to the regression line because they all are more or less clones of one another -- they seem to be doing pretty much the exact same thing -- their chemical formulae are highly similar.

As we can now see all 4 of these modern anti-amyloids are indeed collinear. Aducanumab, Lecanemab, Donanemab and Gantenerumab are all almost exactly where they should be given a linear regression. The 302 high dose Aducanumab in the figure is shown at ~-0.35 (this was one of the alternative CDR-sb values given in the FDA Briefing Document) while the reported value was -0.39. So even the largest deviation is now down to ~ +0.04 CDR-sb. It would be expected that the upcoming phase 3s should also line up quite well with expectations (barring any changes to the patient population mix, etc.).

Such strong alignment goes beyond merely confirming the efficacy of anti-amyloid treatment. It demonstrates that the treatment is effective under heavy constraining conditions. It is interesting to note that in the dona phase 2 article they provide a 95% CI of -0.83 to 0.12 for the reported result of -0.36. Yet, in the adjusted value of -.47 determined above we found that it deviated from expectation by only +0.01 (-0.46). The deviations for the other trials were also quite small.

Why (or how) could they be so accurate? Why is the 0.95 CI so far off? From the figure the results are closer to being within 0.02 to 0.03 deviations. How is that possible? Psychometrically, there is probably good agreement distinguishing a 1 CDR-SB patient and a 1.5 CDR-sb patient. If you have a 1,000 AD patients in a trial arm, then the average CDR-sb will not be up to 0.48 CDR-sb deviation at the 95%, but much much smaller. If you can resolve down to 0.5 CDR-sb, then perhaps 2 *(0.5/ 1000^0.5) = ~0.0158 *2 = ~0.03 is a better estimate of the expected deviation. This might explain why almost all of the points appear to be exactly where they should be and not far far off the line.
Once again a purely statistical approach is hiding more than revealing the truth. If the anti-amyloids are ineffective, then how is it that ~10 of them line up with near 100% correlation on the CDR-sb versus SUVR axis? All of these trial results are consistent with a very strong linear relationship. More amyloid removal = More cognitive benefit.

This perspective, while possibly not in the same meaning of the purely statistical sense, would help to add considerable confidence to the reported values. For example, the "true" Aducanuamb phase 3 302 high dose result is not likely to have been +0.1 instead of -0.39, but much more likely to have been -0.37. The extremely collinear results shown above essentially require such an interpretation. The amyloid SUVR are objectively determined and highly accurate; the linear relationship to CDR-sb then allows us to estimate the cognitive benefits to the patients.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I am feeling great about where we are now with the anti-amyloids!
This is the time just before everything goes right!
After all of these years we are now right on the edge of effective anti-Alzheimer treatment.

An overwhelming amount of clinical evidence is now approaching shore.
The big ones to watch over the nearish term are:

Donanemab Trailblazer-4 Phase 3 June 17, 2022 (versus Aducanumab, smallish Phase 3)
Lecanemab Clarity Phase 3 September 8, 2022 (with a September top-line readout?)
Gantenerumab Graduate 1 Phase 3 September 23, 2022 (reported as still enrolling)
Gantenerumab Graduate 2 Phase 3 September 21, 2022
Donanemab Trailblazer-2 Phase 3 April 21, 2023
Gantenerumab Phase 3 October 4, 2024

There are even others for example the Lecanemab A3-45; another Lecanemab trial with tau cotreatment has just been announced; there is also the Aducanumab phase 4 ICARE AD which is expected to start in May.

(With the ICARE trial I think an innovation that might be worth considering is to use the patient wait registries as a pre-screen. Quite a bit of money was spent on these registries and yet they never seemed to be used that much. With a pre-screening phase you would have an idea of the cognitive trajectory of patients before entering the actual treatment phase. Innovation really is the key with these trials-- it is easy to replicate a previous trial, though pushing forward with new ideas and new research questions is what truly drives the science to the next level.

Patient prescreening could have a range of benefits. For example, we saw with the Aducanumab phase 3s, that some of the patients had rapid progression almost immediately after trial enrollment. This caused a considerable confusion in the results as some of these rapid progressors carried the average cognitive decline of 25 typical progressors. How does it make sense to have a trial where some patients have a 10 point CDR-sb decline while the "average" patient declines by 0.39? With such distortions "average" should probably be thought of more as the median than the arithmetic average. A patient pre-registry could be a great way to reduce this problem. It would also allow for an individual level of comparison between treatment and control. At the level of the patient this would be what they would experience and what would seem meaningful to them: How does treatment affect me?

There was also the reverse problem that a fair proportion of the patients did not decline or even improved (especially those on placebo). At a certain point, one has to consider Alzheimer patients who do not decline as not Alzheimer patients. In the trials this also added noise into the dataset. With a patient pre-registry, one could select those patients who demonstrated expected cognitive decline for enrollment.

I guess another funny part is that the preregistry period could also be added into the placebo data analysis. Basically, everyone would be on placebo during the preregistry timeframe and this would be bonus info. If you had a large preregistry group, then you could possibly randomly sample from this group and have even more statistical leverage.)
{CMS might have different institutional contacts and motivations that could allow such a pre-screening registry for any trials they might start.}

All the yelling and screaming about more clinical evidence needed will seem highly misplaced once it is realized that
some of the future CMS trials might not have even started before definitive evidence of anti-amyloidal efficacy has been reported. The irony here is that after all these years of want we are now approaching too much information! A surfeit of results! It's embarrassing. It's like we don't even need the money -- momo mopro. Those calling for better clinical evidence to use scarce public dollars wisely, might soon realize how unproductive and wasteful large publicly funded anti-amyloid treatment trials are when the answer is now so close at hand.

It's not that clear what relevance any CMS future clinical trials would have in answering the question about
anti-amyloid efficacy: A definitive answer is now likely only months away.)

(It is somewhat disappointing, though, that there will be a largish data hole from April 2023 to October 2024. We are currently in such a hole now since the publication of the Lecanemab phase 2 last ~April until this September with the large phase 3s. I think this was a strategic error not to have more of a constant supply of new anti-amyloid news as it has given those who have spread doubts a free hand. If we had had even 200 person positive phase 2 results reported every ~4 months over the last year, then such doubt would have been difficult to conjure. One strategy could have been to simply break up the large trials like Clarity into 2; with an earlier reporting of part 1. The analysis plan could have stated that they would be meta-analyzed once all the information was in. Hopefully, now that anti-amyloids have largely been proven to be effective, we will see essentially constant reporting of at least phase 2 trials. As a comparison there are currently 29 trials recruiting or about to recruit for Aricept. We might soon see that level of saturation research for anti-amyloids!

How did we wind up in the data drought? Monday morning quarterback time-- why weren't even more anti-amyloid trials started 5 years ago? Those in the know knew 5 years ago that anti-amyloids were effective. Why didn't this initiate a near continuous launching of trials? As we can see above once products arrive on the market (with the anticholinesterases drugs even products that are not that effective) research is then almost non-stop, though perhaps not all that informative. Meanwhile for the anti-amyloids having even one or two more phase 2 results published would have been debate stoppers.) Of course, endless research is always so much easier to finance when money is flowing into the company.

I was pleased to read that the management decision seems to be to stay with accelerated approval for Lecanemab.
I had thought that perhaps there might be an opt out for a more conclusive result before going to the FDA (in light of the recent preliminary draft of the CMS policy; that is, go for full approval on the first round and not accelerated approval) in order to completely end the discussion about anti-amyloid efficacy. For patients having to wait yet more months for clarity would have been very difficult. The current game plan seems to be to file with the FDA, have the topline read out positive and then be granted accelerated approval soon after. Perhaps Lecanemab could then be resubmitted for full approval once all the results for Clarity are compiled. Increasingly this scenario of a near term accelerated approval for Lecanemab would seem to be the best option for AD patients. The one hold back is that the CMS' coverage decision was worded to apply to all anti-amyloids. Lecanemab is obviously a superior product that has shown better safety, and substantial and clinically meaningful efficacy (especially in epsilon 4s). CMS should be aligned with this rapidly approaching reality and remove the coverage with evidence condition for Lecanemab and other future anti-amyloids. This evidence will soon be available and the patient advocacy groups, AD family and patients will then want rapid access to this new class of AD treatment. Most of the logic of the CMS' coverage policy
is not clearly applicable to the next generation of anti-amyloids.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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I want to give the CMS document a ramble through; I have tried to stay away from more rambling and incoherent posts this year (We got this one!), though there might not be too many more chances to do so in the future.

I will go in depth into the CMS' coverage decision
https://www.cms.gov/medicare-coverage-d ... &NCAId=305

Decision Summary
"A. The Centers for Medicare & Medicaid Services (CMS) proposes to cover FDA approved monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease (AD) under Coverage with Evidence Development (CED) in CMS approved randomized controlled trials that satisfy the coverage criteria specified in Section C below, and in trials supported by the National Institutes of Health (NIH). All trials must be conducted in a hospital-based outpatient setting."



In this and subsequent posts I have highlighted my responses in color versus the black text of the CMS document. This makes it easier to see what I added.

That is a fairly startling open gambit. All "FDA approved monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease (AD) under Coverage with Evidence Development (CED)"?

That really does not seem like a great idea. As a first edit it would seem much more sensible to rephrase that as:

"A. The Centers for Medicare & Medicaid Services (CMS) proposes to cover the FDA approved monoclonal antibody Aducanumab for the treatment of Alzheimer’s disease (AD) under Coverage with Evidence Development in CMS approved randomized controlled trials that satisfy the coverage criteria specified in Section C below, and in trials supported by the National Institutes of Health (NIH)."

Assuming that uncontestable evidence in favor of anti-amyloid efficacy will not emerge might not even stand over the next several months. Drawing a line in the sand right on the edge of the waterline would not seem to be strategically wise.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Oh man, the forum software ate my post!
Err!

The APOE4 forum until now has been quite good about allowing me to click back to sign in while keeping my posts in progress. This time it ate my post and didn't give it back! ERR!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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B. "For any CMS approved trials, or trials supported by the NIH, that include a beta amyloid positron emission tomography (PET) scan as part of the protocol, it has been determined that these trials also meet the CED requirements included in the Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease NCD (220.6.20), and one beta amyloid PET scan will be covered per patient, if the patient did not previously receive a beta amyloid PET scan."

Err! I will give a brief summary from memory of what I just wrote.

One beta amyloid PET scan would seem insufficient. What are you supposed to do with one PET scan? How do you calculate delta SUVR with only one scan? What can you do with only a right hand glove?
The FDA noted that there was strong (though not conclusive) evidence of a link between amyloid reduction and cognitive benefit. Isn't the CMS interested in clarifying this relationship? In order to make such a clarification two scans would be needed to calculate delta SUVR.


C. Covered Indications and Coverage Criteria for CMS Approved Trials
1) "A CMS approved randomized controlled trial may be extended to a prospective longitudinal study when the randomized controlled trial is completed, and the findings of the randomized controlled trial demonstrate a clinically meaningful benefit in cognition and function. Details of the prospective longitudinal study must be included in the same protocol as the randomized controlled trial."


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

The CMS could consider patient criteria that included pre-MCI -- the potential for massive cost savings or at least shifting cost out of the CMS budget silo. AD costs government over $300 billion (in hard dollars) and is increasing exponentially. Not proactively managing this expense no longer seems reasonable. The dementia pandemic will only escalate through time. However, by moving further upstream and treating early then the entire conveyor belt of new AD patients could be turned off. The neurodegeneration process happens years before cognitive symptoms emerge.
It was seen in early research with aducanumab that those who endogenously make the treatment were highly resistant to dementia and safety concerns never appeared to emerge. It is only waiting for cognitive symptoms and then treating with gram scale doses over an 18 month clinical trial that patient safety is compromised. What was also somewhat of a surprise to me was that naturally present amyloid causes all sorts of medical problems by itself. Even the placebo arms in the anti-amyloid trials have demonstrated ARIA and other side effects (e.g., amyloid is known to be a prominent risk factor for strokes).

Amyloid is clearly a neuro-toxin. Why wait for frank cognitive impairment to do something about it? Neuroimaging has shown that years before MCI, neurodegenerative changes occur in those with amyloid. Substantial cost savings could accumulate if amyloid were removed earlier than later. This might also remove the budgetary cost from CMS' silo to someone else's.

A trial with APOE 44s in the Pre-MCI setting would be a great idea. 44s have a near dominant level of dementia risk. A clinical trial with 1,000 44s without a placebo arm could be highly informative. Moving the yardsticks upfield could result in large long term savings.




•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.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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(b) Research Questions
CMS approved trials must address, at a minimum, the research questions below:
•Does use of monoclonal antibodies directed against amyloid for the treatment of AD result in a statistically significant and clinically meaningful difference in decline in cognition and function?

Notably the FDA viewed any statistically significant difference in decline in cognition as clinically meaningful.
The Emerge high dose arm did find such a statistically statistical difference for the high dose arm (p=0.0120), though this was in the overall population seen as marginally clinically significant. Nevertheless, the epsilon 4s in the trial did receive clinically benefit and other anti-amyloid trials have also shown clinically relevant results.


•What are the adverse events associated with the use of monoclonal antibodies directed against amyloid for the treatment of AD?
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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(c)Study Requirements
The diversity of patients included in each trial must be representative of the national population diagnosed with AD.

Often the clinical strategy of pharma is to be more restrictive with clinical populations before approval and then more have focused representation in post-approval trials. Given this usual approach, the diversity suggestion above would be less than what is typical and not more.

Counter-intuitively allowing for non-representative samples could then actually be more inclusive. One could imagine more of a bespoke series of clinical trials that considered a series of specific demographic populations and/or clinical questions that could help provide valuable insight. Unfortunately, the phase 3? trials as suggested by CMS only would be designed to explore population scale questions, though it would be of great interest to take a Bayesian approach and drill down to study more granular demographic groups which did best with treatment and also to try a more stratified strategy. For example in the Aducanumab phase 3s it was found that males, epsilon 4s, certain ethnicities etc. appeared to do better. Also the PRIME phase 1 for aducanumab anti-amyloids reported almost 70% benefit over placebo. Such results should not be dismissed casually as wrong: it is quite possible that subgroups do have such large benefits on anti-amyloids. Of further interest is that the PRIME patients were all American; perhaps there are specific populations in the US that do especially well? Why not actively search out those groups that demonstrated the largest benefits and enroll enough patients that these benefits are real and not statistical noise?

Seeking out such subgroups with Bayesian adaptation could allow for efficacy results to be found much more rapidly. It does seem plausible that such differences do exist; moving away from a strict national sample perspective could help identify them.

There are also many other very interesting research questions that could be asked with a more boutique style of investigation. For example, I think it would be fascinating to offer treatment to everyone with AD in a smallish-medium sized town/city. What will the implications of a dementia free society be? I think it would be of considerable importance to research this post haste. The focus on always thinking of health as a problem of the individual and not the community is seen all too often in typical clinical designs. Ironically, the ME versus WE perspectives of life underlie major fault lines in global culture and are one of the more obvious dividing lines that the CMS is trying to address with its diversity policy.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Additionally, any CMS approved trial must adhere to the following standards of scientific integrity:

a.The principal purpose of the study is to test whether the item or service meaningfully improves
health outcomes of affected beneficiaries who are represented by the enrolled subjects.

The rationale for the study is well supported by available scientific and medical evidence.
b.

The study results are not anticipated to unjustifiably duplicate existing knowledge.

c.
A(sic T)nticipated number of enrolled subjects is sufficient to question(s) being asked in the National Coverage Determination.

d.
The study is sponsored by an organization or individual capable of completing it successfully.

e.
The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it is also in compliance with 21 CFR Parts 50 and 56. In addition, to further enhance the protection of human subjects in studies conducted under CED, the study must provide and obtain meaningful informed consent from patients regarding the risks associated with the study items and/or services, and the use and eventual disposition of the collected data.

Open science. (This sentiment is duplicated further down in this post.)

There is an opportunity with funded trials to comprehensively report the entire dataset adhering to open science guidelines. Typically pharma funded science is highly opaque; only partial datasets are ever publicly disclosed as the information is thought of as being a trade secret. This was seen in the FDA Briefing Document for Aducanumab when there were disclosure gaps that made it difficult to understand some of the results. This led to a great deal of confusion and allowed some to introduce doubt into the efficacy results. For example, the individual level regression of CDR-sb versus SUVR showed an improbable roller coaster relationship. It was only later disclosed in a later FDA document that these regressions were done without regard to covariates. Such regressions are then meaningless. Yet, this is one of the more repeated fallacies that has entered the discussion about Aducanumab's efficacy.

Open science would allow a more detailed investigation of the data (perhaps even by incompetents like myself). What has been found time and time again when free data access occurs greater insight can emerge. While there might be privacy concerns, these would seem highly manageable. One could add in a certain smudge factor so that personal identification would be unlikely. Patients could give their informed consent for such disclosures.





f.
All aspects of the study are conducted according to appropriate standards of scientific integrity.
g.
The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.

h. The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Such studies may meet this requirement only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options.

I would return to the idea above of including those with pre-MCI. In my family experience with Alzheimer's, our loved one was not truly cognitively healthy even years before the official diagnosis. In many ways this was a much more difficult period to cope with pre-dementia than in the later stages when the cognitive decline was self-apparent.
I suspect that transferring the psychopathology until the children of those with dementia in the early stages is fairly common. Such transfer likely causes an overwhelming amount of social harm. Pretending that such harm does not exist is not responsible and does not protect the children of dementia who exist in these difficult home environments. This would be another strong argument to proactively recognize the cognitive issues that exist in the pre-MCI state and fund intervention trials for this stage of the illness.



i.
The clinical research studies and registries are registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. Registries are also registered in the Agency for Healthcare Quality (AHRQ) Registry of Patient Registries (RoPR).

j.
The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 12 months of the study’s primary completion date, which is the date the final subject had final data collection for the primary endpoint, even if the trial does not achieve its primary aim. The results must include number started/completed, summary results for primary and secondary outcome measures, statistical analyses, and adverse events. Final results must be reported in a publicly accessibly manner; either in a peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with negative or incomplete results).


I think that an even stronger disclosure policy could be considered. Often with pharma the clinical trial results are largely considered to be corporate assets that are not fully divulged in readouts. So with the aducanumab documents that were reported in the FDA a great deal of the detail was deliberately smudged from public view.
The CMS intends to fund clinical trials with public moneys. In a sense the complete results belong to the people
who funded the trials-- i.e., the public. This would seem to imply an open science policy- fully disclose all results from the trial. Everything! Of course, within the constraints of privacy considerations. Though with anonymized amyloid scans, cognitive readouts etc. the legitimate requirement for privacy is not obvious. Being somewhat vague about certain of the demographic features could provide reasonable levels of protection against identification.

If given the opportunity I would likely explore such a dataset myself as long as onerous access restrictions were absent. Such an open science policy could produce unexpected benefits. When you allow interested people (even those such as myself who are somewhat incompetent) to explore data it has been found that unforeseen discoveries can be made.

It is not difficult to imagine such discoveries with an anti-amyloid treatment.
For example with the aducanumab results, even the FDA Briefing document reported regressions at the individual level between CDR-sb and SUVR. However, it was later noted in another FDA document such individual level regressions are not valid because covariates were not considered. It is only at the group level that valid correlations can be calculated (This is what the thread has done with the various readouts for the anti-amyloid trials). However, if CMS were to report more comprehensive demographic details for patients in the clinical trials, then isorisk regressions could become plausible and more insightful interpretations of the dataset could occur. As it is, pharma seems reluctant to make such disclosures; yet, a more open science stance taken by the CMS might help to provide leadership on this issue. Perhaps pharma could be convinced that their self-interests were best served by also adopting such a more radical open science policy.



k.
The study protocol must explicitly discuss beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.
l.
The study protocol explicitly discusses how the results are or are not expected to be generalizable to affected beneficiary subpopulations. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.
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