According to comments submitted on the draft guidance to the U.S. FDA, guidelines for developing drugs to treat early Alzheimer's disease should focus on factors such as cognitive changes and brain atrophy.FDA Updated in March This YearIts draft guidelines for the development of early Alzheimer's disease drugs in 2018. The updated guidelines include biomarkers and outcome measures that can be used to select clinical trial participants. Another significant change in the guidelines is that the FDA has stated it will allow the use of endpoints based on cognitive assessments or surrogate endpoints.The feedback collection period for the updated guidelines ended on May 13, with 74 feedback submissions received from various parties.Johnson & Johnson expressed support for the revision of the guidelines but requested the FDA to clarify the use of cognitive measurements and modeling methods that can be applied to diagnose early Alzheimer's disease. The company stated that, in some cases, the "presumed pattern of meaningful change" mentioned in the guidelines may be more convincing than a single test to determine whether a patient has early Alzheimer’s. The company emphasized that the guidelines should recognize that changes may take time to become apparent. In the early stages of the disease, it may manifest as a single or limited cognitive deficit.Johnson & Johnson also requested the FDA to clarify in the guidelines that the understanding of Mild Cognitive Impairment (MCI) is continuously evolving and should be based on the latest research and agreements with regulatory authorities. Johnson & Johnson stated, "We appreciate the FDA's position that biomarkers indicating cognitive changes alone may represent an opportunity to provide sufficient support for market approval. There is no consistent, clear definition in the field regarding early mild cognitive impairment. However, as research in this area progresses, further discussions with the FDA are necessary to better define the guidance for transitions in the early stages of the disease."Johnson & Johnson also asked the FDA to clarify its thoughts on using modeling approaches such as Quantitative Systems Pharmacology (QSP) models and disease progression models to establish endpoints based on the stage of a disease. Johnson & Johnson added, "It would be helpful if the guidelines included some considerations for using models to support approval, such as combination therapies and the validation of surrogate endpoints."The organization "Coastal Psychoanalysis" (SOTC), which covers neurodegenerative and neurodevelopmental disorders, also submitted feedback on the updated guidelines. It stated that the FDA's decision to separate the requirements for Activities of Daily Living (ADL) from the early stages of Phase 1 to Phase 3 in the evaluation of Alzheimer's patients in the updated guidelines is commendable, as it will ensure higher clinical reliability.SOTC stated, "ADL in very early-stage patients is unlikely to show sufficient differences to guarantee statistically significant results. In fact, requiring ADL at an early stage may only introduce confusion to the final outcomes of clinical trials and could potentially lead to clinical failure of the compound." SOTC urged the FDA to focus on pathophysiological changes, particularly brain atrophy, when evaluating early Alzheimer's disease. SOTC pointed out that data variations in trials assessing monoclonal antibodies (e.g., Aduhelm, Leqembi, and donanemab) demonstrate the challenges of evaluating AD based on amyloid levels.SOTC stated, "Brain atrophy is the most obvious, most testable, and possibly the most meaningful modifiable symptom of Alzheimer's disease. In our study, researchers found that the annual whole-brain atrophy rate in MCI patients increased by 140% from baseline, while in clinical Alzheimer's disease patients, the annual whole-brain atrophy rate increased by more than 280% from baseline."SOTC believes that the degree of brain atrophy is significantly higher in patients with MCI and Alzheimer's disease. If Alzheimer's drugs cannot markedly improve or stabilize brain atrophy, the drugs may not be effective.SOTC stated, "We are confident that the draft guidance omits specific pathophysiological factors to welcome countless targets and outcomes for various disease states; however, we believe that without further guidance on target-level outcomes, the industry and key sponsors will continue to focus ineffectively on the amyloid hypothesis. In summary, we hope regulatory agencies will consider adding specific pathophysiological objectives to the guidance, and ideally include these targets’ hierarchy in a manner most meaningfully correlated with patients' quality of life and lifespan."
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