Value-based assessment of pharmacodiagnostic testing from early stage development to real-world use.

Disease etiology may be regarded as a consequence of both genotypic and biochemical phenomena, which impact individual patients in different ways. Disease prognosis, beneficial treatment response, and susceptibility to adverse drug effects are often intimately tied to individual biology. Clinical and genetic biomarkers applied individually or in concert are increasingly used to stratify patient populations in terms of prognosis, therapeutic benefit, or safety. As a result, clinical trialists are challenged to design studies that reflect these determinants of outcome, to optimize the patient's eventual clinical course both in the trial and in actual practice. These designs are informed both by preclinical studies and by real-world research that can establish proof of concept for a novel biomarker and provide a basic understanding of the relationship between biomarker and clinical outcome. As clinical and real-world studies unfold, a deeper understanding of the nature of the biomarker and its potential uses in drug development is gained. Specifically, one can eventually define the biomarker as prognostic (i.e., predicts disease progression), predictive (predicts treatment response or adverse outcome(s)), or exhibiting both prognostic and predictive properties. One must further validate the performance of these emerging biomarkers, again in both the trial and real-world environments. The eventual adoption of the biomarker as a useful pharmacodiagnostic test is premised upon this early translational research. In this article, the development and validation of predictive and prognostic biomarkers is discussed by using selected examples that highlight factors contributing to the valuation of biomarkers and their application to personalized medicine in the real world.

The epidemiology of Alzheimer's disease: laying the foundation for drug design, conduct, and analysis of clinical trials.

Epidemiological studies increasingly inform Alzheimer's disease (AD) public health impact, prevention strategies, drug targets, therapeutic interventions, and clinical trial design. For this reason, the Alzheimer's Association Research Roundtable convened an international group of AD experts with experience in conducting both observational and clinical trials for a meeting on October 19 and 20, 2010, in Washington, DC, to discuss the role of epidemiologic studies in AD research and therapeutic advances. Topics included wellness markers and risk factors, with a focus on special populations such as those at elevated risk, super agers, and underserved populations. Discussions also highlighted lessons learned from observational studies of aging, cardiovascular disease, and other disease areas, as well as how new technologies have enabled the gathering of data relevant to drug development and clinical trial conduct.

Comparison of "Word" vs. "Picture" Version of the Free and Cued Selective Reminding Test (FCSRT) in Older Adults.

BACKGROUND: This study examined the psychometric relationship between the Word and Picture versions of the Free and Cued Selective Reminding Test (FCSRT) and developed an equation for score conversion. METHODS: 187 participants were administered the FCSRT-Picture and FCSRT-Word on two visits using a randomized counterbalanced design. RESULTS: Participants had a mean age of 82.1 (sd=5.4) and mean education of 14.5 (sd=3.3) years. Mean FCSRT-Picture Free Recall score (mean 33.0, range: 17-44) was 7.9 points higher than the Word score (mean 25.1, range: 3-43). The Picture and Word FCSRT correlations for Free Recall and Total Recall were r=0.56, p<0.01 and r=0.46, p<0.01, respectively. DISCUSSION: The Picture and Word versions of the FCSRT were moderately associated in a sample of cognitively normal older adults. The score mean differences and variability between FCSRT-Picture and FCSRT-Word indicate that their scores should not be considered equivalent.

Screening for predementia AD: time-dependent operating characteristics of episodic memory tests.

OBJECTIVE: Data from the Einstein Aging Study (EAS) were used to prospectively evaluate the free recall score from the free and cued selective reminding test (FCSRT-FR) and logical memory I immediate recall (LM-IR) subtest of the Wechsler memory scale-revised for prediction of incident Alzheimer disease (AD) dementia among individuals from a community-based cohort with memory complaints. METHODS: Analyses included 854 participants, age ≥70 years, who initially had no dementia, and had memory complaints. Clinic evaluations were completed annually and AD dementia was diagnosed using standard criteria (n = 86 cases; average follow-up 4.1 years). Time-dependent receiver operating characteristic analysis was used to evaluate the prognostic ability of FCSRT-FR and LM-IR for incident AD over various durations of follow-up. RESULTS: For identifying those with memory complaints who will develop incident AD dementia over 2-4 years, the FCSRT-FR had better operating characteristics than LM-IR. APOE ε4 status, age, and education did not affect cut points; however, positive predictive values were higher among APOE ε4-positive individuals. CONCLUSIONS: For follow-up intervals of 2-4 years, the FCSRT-FR is more predictive than the LM-IR for identifying individuals with memory complaints who will develop incident AD. APOE ε4 status improves positive predictive value, but does not affect the choice of optimal cuts.

Impact of early intervention and disease modification in patients with predementia Alzheimer's disease: a Markov model simulation.

BACKGROUND: Early screenings involving biomarkers and use of potential disease-modifying therapies (DMTs) may have significant humanistic implications for treatment strategies in Alzheimer's disease. METHODS: Markov models simulated transitions of patient cohorts beginning in predementia, a hypothetical early stage of Alzheimer's disease marked by objective cognitive impairment/memory complaints without functional impairment, and followed for 10 years. Hypothetical cohorts of 10,000 patients included those who were treated with standard of care (donepezil) upon reaching mild-moderate Alzheimer's disease, a DMT in predementia, and a DMT in mild-moderate Alzheimer's disease. Transition probabilities were based on data from the Alzheimer's Disease Neuroimaging Initiative and published clinical data, and estimated for the hypothetical DMT. In each disease stage (predementia, mild, moderate, or severe), time was computed and costs were estimated using literature review and published data, and published data provided mortality rates. The impact of screening was evaluated using positive predictive value (patients identified as predementia truly at risk for transition to dementia). RESULTS: Earlier treatment yielded modest gains in total life-years; however, the distribution was skewed towards milder disease. Assuming a 25% reduction in the annual risk of progression, treating predementia patients with DMT increased life-years in predementia to mild states on average from 3.2 to 4.2, while life-years spent in moderate-to-severe Alzheimer's disease decreased from 2.6 to 2.2. Average time in the community increased from 4.4 to 5.4 years, while time in long-term care declined from 1.3 to 0.9 years. This impact grows as the advantage of the novel agent increases. Screening accuracy had significant implications for cost-effectiveness. CONCLUSION: If screening can accurately identify predementia patients at risk for progression, earlier treatment with DMTs has the potential benefit to patients of prolonging time in milder disease, reducing time spent with more severe disease, increasing time in the community, and reducing time in long-term care.