LuMind/NTG Drug Prescribing Equivalency Project, etc.
Prescribing Criteria for Anti-Amyloid Drugs and AA Alzheimer's Disease Clinical Criteria
NTG and the LuMind IDSC Foundation Advisory on Determining Alternative Eligibility Criteria for Access to the New Class of Anti-amyloid Drugs to Treat Alzheimer's Disease
Exciting progress has been made in the field of Alzheimer's disease treatment. The US Food and Drug Administration (FDA) has provided for accelerated approval for two drugs, aducanumab and lecanemab, for individuals with mild cognitive impairment or early-stage dementia caused by Alzheimer's disease. Expectations are that the FDA will give traditional approval for these drugs in July 2023. Another drug, donanemab, is currently under review, with more expected to follow. However, to prescribe these drugs requires the clinician to address specific eligibility criteria in their patients.
Current FDA label and state prior authorization criteria (for Medicaid) for Aduhelm and Leqembi lack national standardization and provisions that permit the inclusion and assessment of individuals with a history of an intellectual disability, including adults with Down syndrome. Criteria defining treatment eligibility for patients with sporadic AD focus on age, exclusion of non-Alzheimer’s causes for dementia, demonstrated cognitive impairment due to mild cognitive impairment or mild AD, biomarker indicators of amyloid plaques presence, and exclusion of non-Alzheimer’s originated causes for cognitive decline. The issue for Down syndrome-associated Alzheimer’s disease (DS-AD) is that the specific methods recommended to identify dementia in the sporadic AD population may not be effective for quantifying cognitive declines against a background of pre-existing impairments, pointing to a need for other methods specifically adapted for adults with Down syndrome.
Complicating standardization is the peculiar way that in the United States medication and payment approval occurs. Pharmaceutical firms file applications for approval of a trialed drug to the FDA, which then evaluates the application and trial outcome data and either disapproves or approves the drug, in this case, an Alzheimer’s therapeutic. Another federal agency, the Centers for Medicaid and Medicare Services (CMS), serves as the approval agent for covering the cost of the medications for eligible persons (i.e., Medicare and Medicaid eligible adults). This federal payer agency which covers payment for the Alzheimer’s treatments has not provided standardized guidance, as it is waiting for the FDA to provided full traditional approved before authorizing Medicare to cover payments for both FDA approved drugs (see note below). Currently, payment is only authorized for those adults enrolled in clinical trials.
In anticipation of eventual full approval and to cover those patients with private insurance or other sources of funds, the individual states have developed their own requirements for determining eligibility. While attending to the core criteria (exclusion of non-Alzheimer’s, cognitive impairment, and presence of amyloid), states have used a variety of objective measures. [See chart of state prescribing criteria taken from the full report].
In determining eligibility, clinicians must assess patient characteristics and use defined instruments to evaluate clinical cognitive impairment. In Florida, for example, eligibility criteria include a Clinical Dementia Rating (CDR)-Global Score of 0.5, Mini-Mental Status Exam (MMSE) score between 24 and 30, objective evidence of cognitive impairment, and a positive amyloid beta plaque PET scan. To exclude other causes of dementia apart from Alzheimer's disease, clinicians must document factors such as vascular issues, Lewy bodies, and frontotemporal conditions. Additionally, a baseline assessment of disease severity using objective measures like the MMSE, ADAS-Cog-13, ADCS-ADL MCI0, and CDR-SB is necessary. For example, in Pennsylvania, confirmation from at least two of the following is required: MMSE score of at least 24, Montreal Cognitive Assessment (MoCA) score of at least 18, or Global Clinical Dementia Rating Scale (CDR) score of 0.5.
Consensus Statement
An expert working group, following review of issues faced by adults with Down syndrome (DS) with accessing the new class of anti-amyloid drug for mild cognitive impairment and early Alzheimer’s dementia with respect to promoting equity in access, has proposed actions to improve access. Adults with Down syndrome have an estimated lifetime risk of up to 90% for Alzheimer’s disease, which contributes to over 70% of their deaths. Adults with Down syndrome will face multiple years delayed access to these disease modifying treatments compared to other at-risk populations, because of state authorization prescribing criteria that excludes them. Without urgency in altering these criteria, potentially a generation of aging adults with Down syndrome will be deprived of access to new treatments. State drug formulary committees’ prescribing criteria currently omit specific mention of adaptations or reasonable adjustments that would enable adults with Down syndrome to access these treatments, once they are approved for use.
To shorten the time for access and avoid delay in treatment, the working group recommends access through two actions: (1) States and other payers adopt the proposed DS-focused equivalency criteria as soon as possible; and (2) Phase 4 clinical trials in adults with Down syndrome be undertaken with similar urgency so that clinicians gain information on the safety of this class of drugs for adults with DS.
The working group recommends a series of wording changes to reflect equivalencies in the prescribing criteria, offers substantiation for such changes, and calls upon relevant organizations to provide education to prescribers, and for professional associations to issue protocols for guiding prescribers in the use of this class of Alzheimer’s disease drugs.
While these neurocognitive parameters are set for prescriptive approval for neurotypical adults, they are mostly not appropriate for adults with Down syndrome. As there is no baseline standard for innate intelligence in the prescription authorizations, the rationale for exclusion of adults with intellectual disability with documented later age cognitive decline should not be a barrier for treatment. Defining early-stage dementia stemming from Alzheimer's disease in adults with Down syndrome can be challenging, as standard cognitive assessment tools and approaches may not be sensitive enough to accurately detect early stages of the disease in this population. Important is a careful consideration of the unique characteristics and needs of the population of adults with Down syndrome when determining best practices and appropriate instruments for defining "early AD".
Standardized cognitive assessment tools that are typically used for neurotypical adults may not be appropriate or sensitive enough to accurately assess cognitive decline in individuals with Down syndrome, due to their unique developmental and cognitive profiles. Instead, clinicians may need to use alternative assessment tools and approaches that are more suitable for this population, such as functional assessments or assessments of changes in behavior or daily living skills (similar the FAQ [Functional Activities Questionnaire] used with neurotypical adults). It may also be necessary to consider other factors in addition to cognitive test scores, such as changes in functional abilities and behavior, when evaluating cognitive decline in individuals with Down syndrome. With this in mind, a panel of experts carefully considered these issues and recommended alternative measures and approaches for evaluating cognitive decline in adults with Down syndrome.
Another issue is determining baseline for the presences of amyloid beta plaques. Most adults with Down syndrome exhibit the presence of amyloid beta plaques throughout adulthood. However, establishing a baseline for these plaques as a measure of Alzheimer's disease pathology, satisfying PET scan criteria for neuropathology documentation, requires further agreement and research. This aspect was also considered by a panel of experts relative to applications to patients with Down syndrome.
Under current prescribing criteria, clinicians must ensure that patients do not have exclusionary factors such as other medical or neurological conditions contributing significantly to cognitive impairment, recent stroke or transient ischemic attack, poorly controlled diabetes, certain brain MRI findings, or current use of specific medications.
The NTG and LuMind collaborative effort to define equivalencies was designed to address the exclusion of adults with intellectual disabilities and promote their inclusion in treatment, as innate intelligence does not factor into prescription authorizations. The challenge for inclusion of adults with neuroatypical conditions stems from the knowledge that instruments used for general neurotypical populations may not effectively assess cognitive changes in neuroatypical adults, particularly those with intellectual disabilities such as Down syndrome. Normative instruments often underestimate cognitive decline in this population. Determining instrument equivalency becomes crucial as is identifying which instruments can accurately detect brain disease-related decline over naturally occurring aging-related decline.
The NTG and LuMind assembled a working group of key researchers, academics, and others knowledgeable of the assessment for dementia in adults with Down syndrome, as well as the use of biomarkers for assessing neurological changes resulting from the presence of Alzheimer's disease. The Working Group on Criteria for Access to Alzheimer’s Therapeutics for Adults with Down Syndrome was tasked with examining existing criteria used in various states for the sporadic AD population to determine which criteria applied equally to adults with Down syndrome and which criteria necessitated an alternative approach. The key criteria examined included (1) age, (2) prescriber, (3) validated MCI/mild AD diagnosis assessment scales, (4) biomarkers for amyloid positivity, (5) test evidence of cognitive impairment, (6) MRI baseline, (7) and exclusion of non-Alzheimer’s causes for cognitive decline. The working group examined each of these criteria and provided recommended wording for equivalency criteria. The overriding principle was that the wording needed to consider the soundness of science as well as the practicality and availability of resources that would aid prescribers when treating a patient with Down syndrome
With Working Group's effort now complete, the NTG and LuMInd have issued a report in the form of an advisory and statement, the first of several versions to be made available. A family version of the working group's work appeared in Helen, A Journal of Human Exceptionality (see below). The group has also prepared a version that will appear in scientific journal so as to alert the scientific and clinical community of this issue.
The NTG and LuMind IDSC recognize that the approval of Alzheimer's disease therapeutic drugs brings hope to those persons affected by cognitive impairment. While adhering to specific eligibility criteria ensures that these drugs are prescribed appropriately, equity in access and affected by pre-existing conditions needs to be factored in. Further, we recognize that overcoming challenges in instrument equivalency for neuroatypical adults and establishing accurate baselines for amyloid beta plaques will improve the effectiveness of diagnosis and treatment.
Postscript: On July 6, 2023 the FDA issued a full traditional approval for the use of Leqembi and on July 7, 2023 the CMS followed with an announcement the Leqembi will get coverage via Medicare if the patient is enrolled in an approved registry. To provide initial guidance to prescriber in applying the required registry information to adults with Down syndrome (should a prescriber choose to take on a patient with Down syndrome and prescribe this DMT), the NTG/LuMind IDSC developed a draft guidance for completing registry information. For review and comment, a copy of the draft can be sourced here.
To read or download a PDF of the report - click here or on the cover image above.
Connect to LuMind IDSC Down Syndrome Foundation for press release and more information.
Click here for a family friendly explainer developed by the LuMind IDSC Foundation.
6/3/23
Click here to read the popularized version of the effort published in the September 2023 issue of HELEN: The Journal of Human Exceptionality
7/30/23
Postscript: The CMS established a requirement for prescribers to participate in a registry to receive coverage for Leqembi (lecanemab). The CMS hosted registry is one of others, which may be hosted by institution, such as hospitals or patient organizations. The registries will enable CMS to collect information about the long-term benefits or harms of the use of Legembi. One issue that has arisen is the lack of standardization of the information being collected and the question of its utility. For a commentary on this issue, see Socal, Odouard, & Kharrazi (2023), "Ownership and Interoperability Challengess of Alzheimer Monoclonal Antibody Registries."
12/12/23
Click here to read "People with Down syndrome deserve access to Alzheimer’s treatment", which appeared in the Boston Globe, September 18, 2023.
Update - CMS announced Medicare coverage for all eligibles as the FDA has given full traditional approval for Leqembi prescribing (June 1, 2023 and July 7, 2023)
Updated information on international availability of AD disease modifying therapeutics (DMT)
Leqembi™ (lecanemab) has been approved for general use and its payments are covered in the USA for all enrollees in Medicare, and in Japan for adults enrolled in its National Health Insurance program (Igarashi et al., 2023; Japan Times, 2023), but only for those adults with proven MCI or early clinical dementia stemming from Alzheimer’s disease. Eisai, the pharmaceutical firm behind Legembi, has submitted applications for approval of use of lecanemab in12 countries or regions, including to the European Medicines Agency in the EU (BioArtic, 2023). In Canada, it is under review by Health Canada (Watt et al., 2023). In China and Israel, the applications have been designated for priority review. In China the application was submitted to the National Medical Products Administration (NMPA), and in Great Britain, lecanemab has been designated for the Innovative Licensing and Access Pathway (ILAP), which aims to reduce the time to market for innovative medicines (Biogen, 2023). A third medication, donanemab (Sims et al., 2023), is poised to be approved in early 2024 in the USA as well as in other countries (McKie, 2023). In the UK, in 2024 the Medicines & Healthcare Products Regulatory Agency (MHRA) will decide if lecanemab and donanemab are safe and effective, then the National Institute for Health and Care Excellence (NICE) will decide whether the cost for the medications will be covered. The first conditionally approved Alzheimer's disease modifying medication, Aduhelm™, was withdrawn from use by Biogen as of January 31, 2024 and all existing clinical trials were terminated. Biogen and Eisai will continue supporting Leqembi, their only fully approved Alzheimer's disease DMT in the United States. 2/3/24
Recommendations Submitted to NIA/AA on New Alzheimer's Disease Clinical Guidelines
The Alzheimer's Association has noted that its 2018 criteria for diagnosing Alzheimer's disease would benefit from an updated recognition that the use of biomarkers has taken on more prominence in the contemporary diagnostic process. Several core principles underscore this belief, including:
o Alzheimer’s disease (AD) should be defined biologically, not based on a clinical syndrome(s).
o The disease is a continuum that begins with the appearance of brain pathology in asymptomatic individuals and progresses through stages of increasing pathologic burden eventually leading to the appearance and progression of clinical symptoms.
o The disease is diagnosed in vivo by abnormalities on core biomarkers.
Thus, the National Institute on Aging and the Alzheimer’s Association (NIA-AA) jointly issued draft diagnostic guidelines on diagnosing Alzheimer’s disease in July at the 2023 AAIC Conference in Amsterdam, NL. The draft was accompanied by a request for comments. The NTG submitted comments on August 25, 2023 on the guidelines and proposed that the guideline offer more attention to diagnosing Alzheimer's disease in adults with intellectual disabilities and furthering research on biomarkers in adults with other than Down syndrome.
Open an Explainer on the July 2023 version.
Open a compendium of all comments on the July 2023 version
Open the NTG's comments on the July 2023 version
The Alzheimer's Association (not branded with the NIA's name) subsequently issued a revised version on October 25, 2023, at the Clinical Trials on Alzheimer's Disease (CTAD) conference; again with a call for further comments. The LuMind IDSC Foundation and the NTG collaborated on the content and on November 16, 2023 submitted a joint comments' statement.
Open the Alzheimer's Association's October 2023 draft criteria
Open the NTG/Lumind comments on the October 2023 version
What was the rationale for the absence of the National Institute on Aging's joint aegis on the October version?
According to commentary on criticisms raised after the AAIC meeting about the NIA's joint issuance with the AA, the ALZFORUM reported that "While the proposed revisions have garnered praise from researchers for more accurately reflecting the underlying biology of the disease, they also have sparked criticism for advancing toward clinical use what were previously research criteria. In particular, the American Geriatrics Society called the move to the clinic premature, noting that many uncertainties remain about how well biomarkers predict symptom onset. The AGS also questioned the extent of the National Institute on Aging’s involvement in the working group. The NIA has now removed its name from the criteria, though its representatives continue to advise the group."
The commentary noted that AAIC July 2023 version "generated 64 public comments from practicing neurologists, pathologists, and organizations such as the Gerontological Society of America. There were also comments from advocacy groups, including the National Down Syndrome Society and the National Task Group on Intellectual Disabilities and Dementia Practices, and from industry, such as Biogen and C2N Diagnostics."
Other comments were related to concerns that the NIA was overstepping its role as a research organization and moving in the clinical sphere. This was raised by the American Geriatrics Society, which noted that the NIA had been a co-equal convener in the 2018 NIA-AA criteria effort but was now only taking an advisory role for the 2023 update.
See ALZFORUM article on this issue: ["New Alzheimer’s Diagnostic Criteria Remain ‘Research Only"; 28 November 2023].
See Forbes Magazine article on this issue: [NIH Steps Back from Development of New Alzheimer's Diagnostic Standards; H. Gleckman, 31 October 2023]