Regulatory Science Symposium: Special Populations Session 7: Geriatric Subjects and Trials in the Cognitively Impaired (2017)

1. Background:
   1. Despite risk of cognitive impairment as projected by studies, actual incidence is uncommon before age 70 and mostly occur above 80.
   2. Cognitive impairment trials can range from 6-12 weeks, extend for 4-5 years. Very small differences between placebo and treatment groups, hence research focuses on getting small effects. Amyloid is major target for AD.
   3. Roadmap for FDA approval of drug for AD: less than 100 patients in P1, 200-300P2 (proof of concept), P 3 confirm effectiveness 400-700 patients.
2. Diagnosis:
   1. Heterogeneous population of patients, Ineffective diagnosis.
   2. Mild Cognitive Impairment (MCI)/(Prodromal AD): same intellectual impairment but low functional impairment
   3. Preclinical AD: Brain pathology but very little cognitive and functional impairment
3. Preclinical AD concept:
   1. Identification of Preclinical AD: Patients who think they have memory impairment, use biomarkers.
   2. It is staged into three:
      1. Asymptomatic amyloidosis- High PET amyloid tracer retention
      2. Amyloidosis + Neurodegeneration – Neuronal dysfunction on FDG-PET/fMRI, high CSF tau/p-tau, cortical thinning/hippocampal atrophy on sMRI
      3. Amyloidosis + Neurodegeneration + subtle cognitive decline – evidence of subtle change from baseline level of cognition which yields poor performance on more challenging cognitive tests and does not meet criteria for MCI.
4. Vulnerable participants and role of study partners:
   1. Not actually vulnerable but impaired cognitive function makes them vulnerable.
   2. Informed consent requires an assessment of participant’s comprehension of research, participation
      1. what are you being asked to do
      2. what question is this study trying to answer
      3. what are the potential risks of participating,
      4. frequency of visits,
      5. difference between participating and standard medical care
      6. withdrawal procedure.
   3. Surrogates decision maker- advance care directive agent, guardian, spouse, adult daughter/son, parent, sibling, adult grandchildren or next closest relative.
5. Outcomes used in cognitive impairment trials:
   1. Clinical outcomes: ADAS-cog, MMSE, ADCS-ADL, Instrumental ADLs, Global ratings (CDR, CIBIC/CGIC), composites and Neuropsychological tests. Behaviour ratings, quality of life, services utilization and caregiver ratings are considered as well.
   2. Behaviour ratings and Quality of life
   3. Biomarkers: not validated, change over time, not predictive of clinical change.
   4. FDA guidance: Conditional marketing for efficacy over cognitive outcome, MCI-requires single composite outcome for efficacy
6. Targets and drugs for early stage interventions:
   1. Potential targets: food/nutritional supplements like Vitamin E, D, B and DHA, Resveratol, Ginkgo biloba extract and repurposed drugs.
   2. Future: Trial databases to model and simulate proposed trials, targeted designs, personalized approaches to N of 1, basket and umbrella trials and expanded indications.

Accompanying text created by Vaibhavi Chokshi | Regulatory Science Graduate Student Worker | vmchoksh@usc.edu