“Punitive, restrictive and unprecedented”: Global Alzheimer’s Platform Foundation President® John Dwyer Comments on CMS Draft National Coverage Determination

Dwyer calls on Centers for Medicare & Medicaid Services to provide coverage for the entire class of mAb drugs approved by the Food & Drug Administration and future drugs yet to be approved

Washington, D.C. (February 11, 2022) – The Centers for Medicare & Medicaid Services (CMS) proposed plan to limit coverage of an entire class of monoclonal antibodies that targets amyloid for the treatment of Alzheimer’s is discriminatory and represents an approach that lacks consideration for people living with Alzheimer’s and their families. Global Alzheimer’s Platform Foundation^® (GAP) President John Dwyer denounces the CMS draft determination, calling it both “life-threatening,” and “unprecedented.”

“The proposed CMS decision is a direct threat to Alzheimer’s patients and their families,” said Dwyer, a leading national expert on improving and accelerating clinical trials. “The proposed restrictions will deny access to Alzheimer’s disease (AD) treatments for millions of patients and postpone access to Alzheimer’s treatment for at least another 10 years. This is an indefensible attack on patients’ rights to choose to take an U.S. Food and Drug Administration (FDA) approved drug that will disproportionately impact Black and Hispanic Americans who are twice and one-and-a-half times more likely to be diagnosed with Alzheimer’s, respectively.”

“The proposed National Coverage Decision (NCD) is a discriminatory, unprecedented breach of CMS’ regulations and past practices with respect to FDA approved drugs,” GAP wrote in its public comment. “Consequently, it threatens to deprive AD patients of options, treatments available now and similar therapies in the future, allowing millions of AD patients’ conditions to go unabated.” The CMS decision to require all mAb medications targeting amyloid to undergo the same randomized clinical trials (RTC) will create a conflicting set of standards and hurdles for drug development that will have a profound impact on the patients that GAP serves and their families.

This proposed determination from CMS undermines the U.S. Food and Drug Administration’s (FDA) statutory authority to regulate the approval of drugs. The FDA decision to “approve Aduhelm pursuant to the accelerated approval pathway (AAP) was appropriate under the law and good for AD patients,” states GAP. Approval by the FDA is, and should continue to be, the gold standard for drug approval and until now this was undisputed by CMS.

In its comments, GAP writes that the coverage decision promotes a clinical trial structure that will block patients from accessing the class of drugs that could make an impact on Alzheimer’s disease progression. By limiting trials to “hospital settings,” CMS is effectively promoting a clinical trial structure that is designed to fail, as large hospitals are traditionally slow to enroll trial participants and are not effective enrolling participations from a diverse clinical trial population

GAP calls on U.S. Department of Health and Human Services Secretary Xavier Becerra and CMS Administrator Chiquita Brooks-LaSure to rescind the CMS coverage decision so as to allow Alzheimer’s patients, families, and physicians the opportunity to access treatments that will “slow the progression of this heinous and always fatal disease.”

GAP’s position on the CMS decision can be summarized as follows:

The FDA’s use of the accelerated approval pathway (AAP) for Aduhelm was informed, and appropriate.
The NCD proposed by CMS is an unprecedented effort by CMS to regulate drugs in a way that invades the FDA’s jurisdiction and violated CMS’s own regulations and practices.
Coverage with Evidence Development (CED) proposes limiting coverage to patients in a randomized clinical trial will delay access to mAbs for millions of patients for at least 10 years.
The NCD’s fatal impairments are amplified by requiring the entire class of monoclonal antibodies (mAbs) directed against amyloid for the treatment of Alzheimer’s disease to run the same arbitrary RCT set out for Aduhelm.
Alternative forms of CED meant to collect evidence of safety and efficacy really represent an alternative method for restricting access to mAbs
GAP looks to Secretary Becerra and Administrator Brooks-LaSure to rescind the NCD and revert back to CMS’s practice of coverage to label for drugs approved by the FDA pursuant to the AAP.

GAP’s comments are below

February 10, 2022

Mr. Secretary and Madame Administrator:

Thank you for the opportunity to comment on the Centers for Medicare and Medicaid Services’ (CMS’s) proposed National Coverage Determination (NCD). The Global Alzheimer’s Platform Foundation (GAP) is a patient centered organization dedicated to accelerating clinical trials to discover cures or treatments for Alzheimer’s. In furtherance of our mission, GAP has undertaken12 advanced Alzheimer’s disease (AD) clinical trials since 2019. GAP intends to comment on the life threatening and unprecedented NCD proposed by CMS on January 11, 2022.

GAP will summarize its position as follows:

The Food and Drug Administration’s (FDA) use of the accelerated approval pathway (AAP) to approve Aduhelm for the treatment of AD was an informed and appropriate exercise of the authority vested in the FDA by Congress.
The NCD proposed by CMS is an unprecedented and capricious effort to regulate drugs in a manner that invades the FDA’s jurisdiction, violates CMS’s own regulations and long-standing practices, and denies more than a million potential patients’ coverage to label for the first approved therapy for AD in 20 years.
The Coverage with Evidence Development (CED) which proposes limiting coverage to a randomized clinical trial (RCT) for approximately 1,500 patients will delay access to Aduhelm or any other mAbs for millions of patients up to 12 years allowing more than 3 million AD patients to progress in this fatal disease to a point where Aduhelm (or any other mAbs) will be unavailable to provide clinical benefit.
The NCD’s fatal impairments are outrageously amplified by requiring all monoclonal antibodies (mAbs) directed against amyloid for the treatment of Alzheimer’s disease to run the same arbitrary RCT gauntlet set out for Aduhelm.
Any other form of CED purportedly designed to collect evidence of safety or efficacy, such as a registry, will essentially be a pretext for restricting access to mAbs to a few thousand patients and take several years to stand up based on CMS’ documented chronic underperformance in these endeavors.
Therefore, GAP calls on Secretary Becerra and Administrator Brooks-LaSure to rescind the NCD and revert to CMS’s long-standing practice of coverage to label for a drug which was approved by the FDA pursuant to the AAP– thereby giving AD patients, in consultation with their families and physicians, the option to avail themselves of disease modifying therapies that can slow the progression of this heinous and always fatal disease.

Our concerns regarding the NCD and our rationale for urging CMS to provide coverage to label for the class of drugs in question is below.

The FDA decision to approve Aduhelm pursuant to the accelerated approval pathway was appropriate under the law and good for AD patients.

On June 7, 2021, the FDA gave accelerated approval to Aduhelm, a Biogen drug for reducing beta-amyloid plaque in the brain to slow the progression of Alzheimer’s disease. This disease modifying drug is the first FDA approved drug for Alzheimer’s patients in over 20 years—giving newfound hope to people living with Alzheimer’s and their families. They did this pursuant to their authority to accelerate approvals for treatments that address life threatening conditions that otherwise do not have approved treatments. Under FDA’s accelerated approval pathway, the FDA may approve a drug that affects changes in a surrogate endpoint adequate to convince the FDA that it is “reasonably likely…to predict clinical benefit.”¹

Since 1992, the FDA has used the AAP to approve over 270 drugs attacking cancers, HIV and a number of other indications devoid of therapies with patient populations facing certain death as a result². The reasonable likely standard is intended to convey a lower standard of proof of efficacy; thus, a confirmatory trial is required. From a patient’s perspective, Congress has decided that when the data is a close question in life threatening cases, the tie goes to patients.

There is no doubt the approval of Aduhelm was controversial³ and not support by the Advisory Committee that reviewed Biogen’s application. Commentators point out that accelerated approval was not presented to the Committee, and new evidence from Lilly and Eisai from their drugs in this class augmented Biogen’s data supporting beta-amyloid as a surrogate endpoint. Ultimately, the sole authority to approve Aduhelm based on the degree to which it reduced beta amyloid plaque in AD patients was the FDA’s. GAP firmly believes that this decision was well grounded, reasonable, and overwhelming good for patients.

The proposed NCD is a discriminatory, unprecedented breach of CMS’ regulations and past practices with respect to FDA approved drugs. Consequently, it threatens to deprive AD patients of Aduhelm as well as similar therapies in the future and allow millions of AD patients’ conditions to progress unabated.

If this NCD is finalized as drafted, then Alzheimer’s patients will receive the most restrictive NCD for a drug in the history of the agency, as compared to a traditional coverage to label. This is one of many discriminatory and unwelcome firsts:

This is the first time CMS has tried to overrule FDA on an accelerated approval.
This is the first time CMS will breach its own regulations prohibiting the duplication of FDA clinical trial efforts or interfering with the FDA’s processes.
This is the first time that CMS has opined on the cause of Alzheimer’s disease, in conflict with the FDA and the research community generally.
This is the first time CMS has issued an NCD-CED for an entire class of drugs.
And this is the first time that CMS has prescribed an NCD requiring randomized clinical trials for drugs that will take over a decade to conduct as written.⁴

Moreover, to shed some light on some of the draft NCD’s hypocritical hyperbole regarding Aduhelm’s safety (and that of the unseen class), GAP reviewed drugs that were covered by CMS after receiving an accelerated approval from the FDA in the last 10 years. The results of the review show⁵:

75 drugs were approved through AAP from 2012-2022;
All of them received CMS coverage;
24% or 18 of the 75 had a Black Box warning. (Aduhelm does not have a Black Box.)
9% or 7 of the 75 had a REMS. (Aduhelm does not have a REMS.)
Currently, the annual prices of the 75 drugs range from a high of $2.57 million to a low of $336 (a vaccine.) The average annual price is $313,000.
Aduhelm, at $28,200 is in the bottom quartile of the list of prices; 9th lowest of 75 drug prices.
The vast majority of the patient populations for which the drugs in question could be prescribed were less than 20,00 (orphan indications.)
Aduhelm was one of two indications with potential patients of more than 1 million.

In short, CMS issued a punitive, restrictive, and unprecedented NCD on a drug and its whole class. GAP’s research shows that Aduhelm (and by extension the class) is not an outlier on safety, in fact nearly 25% of the other drugs had far more serious safety profiles. And while not within CMS’ legal remit, Congress can rest easy that the price of this drug is in the bottom quartile of drugs covered in the last 10 years. So, if it’s not an issue of safety, and consistent biomarker evidence of clinical benefit was present among all 75 other drugs (all AAP approved), what is it that triggers CMS’ asymmetrical response to this drug class?

GAP thinks the facts show that CMS is refusing to do what is required of it because of the size of the patient population that could qualify for the drug. It is discriminating against AD patients because there are so many of them. For the first time in the history of the agency, the fact that more than a million patients could benefit from a drug has triggered a never-seen-before RCT based CED that would limit paid drug access to a few thousand patients. CMS is rationing AD patients’ care. It is an unconscionable policy that cannot stand.

The proposed NCD proposes a RCT structure that is designed to fail. It is fair to characterize it as an ornate duplication of FDA Phase 3 pivotal trials or Phase 4 confirmatory trials that will only succeed in blocking patients from obtaining access to mAbs that will slow the progression of their disease.

The NCD proposes a RCT that has been faulted as poorly conceived by groups that are both for and against the FDA approval of Aduhelm. Among the “consensus” elements that are most ill-advised about the RCT concept, are:

The RCT duplicates protocol development and designs to measure clinical meaningfulness.
The RCT will be executed by parties unaccustomed to conducting these kinds of clinical studies.
Restricting the RCT to “outpatient hospital settings” will limit the network to roughly 50 tertiary locations.⁶
Such locations historically are slow at activating and enrolling volunteers in RCTs, especially during Covid.
Such locations historically underperform in recruiting diverse populations of participants in volume.
The suggested exclusion and inclusion criteria were uninformed as well as inconsistent with emerging best practices for recruiting diverse populations.
The RCT structure largely shuts out deployment to rural communities.
The number of volunteers needed to populate the RCT would probably not exceed 1,500 and take over 10 years to conduct; resulting in about 1% of the patients that could benefit from Aduhelm receiving the drug during this time.⁷

In summary, the overwhelming majority of the AD community thinks the RCT concept is fatally flawed as proposed and unsalvageable given the time such an effort would require in redesign and execution. CMS should allow the FDA mandated Phase 4 confirmatory trial Biogen will start next month to play out, provide coverage to label while it does, and allow patients and their doctors an opportunity to avail themselves of this drug and the class below.

The NCD’s fatal impairments are outrageously amplified by requiring all monoclonal antibodies (mAbs) directed against amyloid for the treatment of Alzheimer’s disease to run the same arbitrary RCT gauntlet set out for Aduhelm.

It is hard to imagine that CMS, one of the crown jewel agencies of Health and Human Services (HHS), could conceive of such a bad idea as taking a whole class of drugs that offer 1,000,000 patients potential life extending therapies and place them in the same regulatory “tiger cage” that they built for Aduhelm, a structure that will constrict their availability for patients for more than 10 years.

The FDA has and will evaluate each drug application on its individual merits for safety and efficacy and determine whether it merits approval. It will derive a label for each drug to guide patients and physicians on the safe and appropriate use of the therapy.

In contrast, without reviewing the data or FDA decision, CMS intends to offer these approved drugs the same flawed RCT that is being roundly criticized by the AD community. This process will generate different standards and hurdles to coverage than the drug development field has ever seen before. It is inconsistent with CMS statutory authority, its regulations, and its mission to serve Medicare beneficiaries. It is, however a very effective way to ration care to AD patients, and patients with other diseases such as cancer, and it cannot stand.

Moreover, in conversations with CMS, the stakeholder community reports that CMS leadership has advanced a narrative that it will provide accommodations for FDA approved therapies, whether AAP approved or traditionally approved it is unclear, that will avoid the RCT quagmire. These musings talk about “expedited reconsiderations” for example without specificity, accountability, or enforceability. These are empty promises from an agency that prides itself on rigor. Especially when access to life prolonging therapies hangs in the balance.

If CMS, has serious alternative formulations for the class, they should have floated them in the NCD. GAP’s healthy skepticism is based on CMS’ past track record in reconsiderations. The field has waited nearly a year to learn if CMS’ NCD for coverage of BA PET images will be reconsidered. Then, we will wait a minimum of nine months until we learn whether CMS decides to consider the PET decision. Our data shows that on average a CMS reconsideration takes 678 days from the time it is taken up until the time it is decided⁸.

A group of AD experts recently said:

“Every day, an estimated 1,000 people progress from mild AD to moderate AD. Because individuals with early-stage disease are most likely to benefit from therapeutic intervention with mAbs – and progression may make patients ineligible for treatment in the future – it is important to address these concerns quickly.”⁹

CMS needs to understand that 687 days means at least 687,000 AD patients could progress to a point where future therapies will not benefit them. Give AD patients coverage to label for the entire class. CMS cannot and will not guarantee patients a clear process that can possibly warrant this level of human devastation.

Any other form of CED purportedly designed to collect evidence of safety or efficacy, such as a registry, will only succeed in restricting access to mAbs to a few thousand patients and take several years to stand up based on CMS’ past performance in these endeavors.

It is axiomatic that science and clinical practice are improved with the accumulation and sharing of reliable clinical data. In stakeholder meetings with CMS, concepts were discussed regarding other means, such as a CED in the form of a registry, by which the agency might be able to meet its need for evidence of safety or efficacy outside the FDA mandated trials described above. GAP strongly discourages CMS from considering a registry or similar evidence gathering endeavor in the form of a CED that would substitute for the current RCT concept.

In GAP’s experience, there are several elements to a registry that affect their performance, including:

Clear protocols defining how safety and benefit will be measured for the drugs being administered.
Protocols need to be informed and consistent with the extensive benefit/risk discussions the drug sponsor(s) have had with drug approving agencies around the world.
Keeping required data appropriately balanced for the clinical and financial burden on patients and practicing physicians so as not to create a deterrent to patients participating in the registry.
Funding that will allow for creation and scaling of a “state-of-the-art” digital environment—in our estimation an AD registry will ultimately require $50-$100 million dollars.
Interoperability with most of the leading electronic medical records (EMR), clinical trial data collection tools, and other registries.
A registry design with flexibility to amend the protocol as needed to take advantage of new emerging technologies that will inform the field and CMS on how to more precisely detect AD and treat AD patients; and
Generating an adequate pool of patients on a drug to recruit into a registry; GAP believes the field should target 100,000 patients.

GAP full throatedly supports the use of technology like that described above after a mAbs drug receives FDA approval and is covered to label. There are several important initiatives underway in the private and public sectors that represent a fertile opportunity for CMS to meet its evidentiary needs. We call on CMS to work collaboratively with these initiatives outside of a CED to catalyze the process and contribute to their deployment.

GAP does not support any registry or similar information gathering initiative that is undertaken under the guise of a CED. The AD field’s experience in the IDEAS studies demonstrates that CMS is not well organized to deploy these kinds of programs quickly or with the requisite adaptability to stay abreast of the science and technologies underpinning AD research. CMS should provide coverage to label for the whole mAbs class of drugs giving AD patients unfettered access to this class of drugs. CMS should access the robust pool of patients it will have catalyzed to collaborate with the private and public sector entities striving to achieve the same goal that CMS has articulated.

Conclusion:

For all the foregoing reasons, GAP calls on Secretary Becerra and Administrator Brooks-LaSure to rescind the NCD and revert to CMS’s long-standing practice of coverage to label for a drug which was approved by the FDA pursuant to the AAP– thereby giving AD patients, in consultation with their families and physicians, the choice of availing themselves of disease modifying therapies that can slow the progression of this heinous and always fatal disease.

¹ U.S. Food and Drug Administration. CDER drug and biologic accelerated approval based on a surrogate endpoint. Updated December 31, 2021. Accessed February 7, 2022. https://www.fda.gov/media/151146/download.

² Ibid..

³ FDA grants accelerated approval for Alzheimer’s drug. U.S. Food and Drug Administration. June 7, 2021. Accessed February 7, 2022. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug

⁴ Global Alzheimer’s Platform Foundation. Projected Timeline NCD/CED. February 2022.

⁵Global Alzheimer’s Platform Foundation. Review of 75 Drugs Covered by CMS.

⁶ Based on the number of sites in national networks for clinical trials, including the National Institute on Aging-supported Alzheimer’s Clinical Trials Consortium and the Global Alzheimer’s Platform Foundations’ GAP-Net sites.

⁷Based on an enrollment of approximately 1,500 in most commercial therapeutic and NIH-sponsored trials for AD and assuming some trial enrollees are on a placebo or in another non-mAb control arm.

⁸ Centers for Medicare and Medicaid Services. Report to Congress: Medicare National Coverage Determinations for Fiscal Year 2020.

⁹Davis M, et al doi: 10.2174/1567205015666180119092427. PMID: 29357799; PMCID: PMC6156780.