LuMind/NTG Drug Prescribing Equivalency Project
Prescribing Criteria for Anti-Amyloid Drugs
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 recently approved two drugs, aducanumab and lecanemab, for individuals with mild cognitive impairment or early-stage dementia caused by Alzheimer's disease. 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., Medicaid eligible adults). This federal payer agency which covers payment for the Alzheimer’s treatments has not provided standardized guidance, as it has currently declined to authorize payment for both FDA approved drugs, except for those adults enrolled in clinical trials.
In anticipation of eventual 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.
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.
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. It would be important for a panel of experts to carefully consider these issues and determine the most appropriate instruments 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.
Under current prescribing criteria, clinicians must ensure that patients do not have exclusionary factors like 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 is 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 challenges for inclusion of adults with neuroatypical conditions is 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, 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 provide 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.
The NTG and LuMind IDSC recognize that the approval of Alzheimer's disease therapeutic drugs brings hope to those affected by cognitive impairment. Adhering to specific eligibility criteria ensures that these drugs are prescribed appropriately. 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.
To read or download a PDF of the report - click here or on the cover image above