From whippansaw - an important excerpt, see replied to post for more information on ongoing changes in Alzheimer's study.
New Guidance Engenders Debate The FDA guidance defines four stages of sporadic Alzheimer’s disease based solely on clinical and cognitive criteria, without reference to biomarkers. In this scheme, stage 1 has no detectable impairment, stage 2 is marked by subtle cognitive decline, stage 3 by cognitive decline and functional impairment, and stage 4 is dementia. Stages 1 and 2 would be considered preclinical disease, and stage 3 prodromal, researchers noted in Barcelona. Maria Carrillo of the Alzheimer’s Association said the guidance represents two years of effort from a working group that convened in 2015 and used the best data available at that time. As new research refines scientists’ understanding of AD, however, the picture may change again. “The guidance is meant to encourage the field to test hypotheses,” Carrillo said. “Some of the revisions in the guidance are already paying off, and some already need revising.”
Case in point: It is not so clear, after all, whether stage 1 disease actually exists, noted Paul Aisen of the University of Southern California, San Diego. Recent studies have found measurable cognitive decline even in people with sub-threshold levels of amyloid accumulation (Aug 2018 conference news). In people with amyloid encroaching on the brain, performance slides slightly faster over time than it does in age-matched controls, even while cognitive scores remain in the normal range. Thus, all preclinical disease may effectively be stage 2.
However, Aisen noted that the difference in decline is slight in preclinical disease, detectable over three years on a sensitive cognitive battery such as the PACC, and over six years on the CDR-SB. In other words, detecting this modest decline would require either long trials or even more sensitive cognitive measures.
Samantha Budd Haeberlein of Biogen in Cambridge, Massachusetts, would rather see the latter than the former. She celebrated the FDA’s willingness to consider new neuropsychological tools. “Industry welcomes this openness, but we’re not as enthused about long trials,” she noted drily. Others agreed. “The guidance is encouraging,” said Gary Romano of Janssen Pharmaceuticals in Philadelphia, adding, “The catch is to demonstrate a relationship between the early and late manifestations of disease.”
Researchers are committed to going early. As Ron Petersen of the Mayo Clinic in Rochester, Minnesota, put it, “Stage 2 is where the money is." These are people whose cognitive decline can be measured, but who are still early enough in disease that interventions could stem the worst of AD. In the draft guidance, the FDA says it will accept cognitive measures alone as the basis for approval in stage 2. It also says a drug’s benefit must be robust and consistent across multiple domains, and that the application will be stronger if supported by biomarker evidence. Petersen suggested mining longitudinal data to identify other early impairments, such as mild neurobehavioral symptoms, that could strengthen the case for a clinical benefit. “Perhaps we could marry subtle behavioral features with tau pathology,” Petersen said.
Industry faces another hurdle in demonstrating that even a slight slowing of cognitive decline is meaningful to people’s daily lives. Chris Edgar of the U.S./Australian testing company Cogstate noted that the previous FDA guidance used the term “meaningful” only twice, but the new draft guidance mentions it 25 times. “This indicates a shift in focus by the FDA,” he said in Barcelona. Alas, the FDA does not define the term. “We’re some ways from having a consensus on what it means,” Edgar said.
