Cerebrospinal Fluid Biomarkers for Alzheimer's Disease: A View of the Regulatory Science Qualification Landscape from the Coalition Against Major Diseases CSF Biomarker Team.

Alzheimer's disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development.

A randomized comparison of methods of selecting narrowband UV-B starting dose to treat chronic psoriasis.

OBJECTIVES: To compare narrowband UV-B (TL-01 lamp) phototherapy for psoriasis with individual patient starting doses based on minimal erythemal dose (MED) determination vs a standard fixed starting dose and to compare the efficacy of 70% of MED vs 50% of MED starting dose regimens. DESIGN: Single-center, randomized, double-blind, clinical trial. SETTING: Department of Dermatology, Ninewells Hospital and Medical School, Dundee, Scotland. PATIENTS: A total of 210 adult patients (207 of skin phototypes I to III) referred for narrowband UV-B to treat chronic psoriasis. The study was designed to have 90% power to detect a difference of 3 or more treatments to clearance and/or minimal residual activity (MRA) between groups. INTERVENTIONS: Narrowband UV-B phototherapy was given according to 3 standard regimens, differing only by starting dose selection method. The randomly allocated starting doses were (1) a fixed starting dose, (2) 70% of individual MED, and (3) 50% of individual MED. All patients were MED tested to ensure blinding and for safety reasons. MAIN OUTCOME MEASURES: The number of treatments to clearance and/or MRA of psoriasis was the primary efficacy outcome measure, with changes in Psoriasis Area and Severity Index and Psoriasis Disability Index scores as secondary measures. Adverse effects were recorded. RESULTS: There were no significant differences in the number of treatments to clearance and/or MRA across all 3 groups or in the percentages achieving clearance in each group. More uncomfortable erythemas occurred in the 50% of MED starting dose group (39%) than in the 70% of MED starting dose group (24%) or the fixed starting dose group (24%) (P=.07). CONCLUSIONS: The methods of determining the starting dose in this predominantly skin phototype I and II population, treated 3 times weekly, with a 20% followed by 10% incremental reduction in dose, did not significantly influence the effectiveness of treatment. Had there been a clinically important difference in efficacy, we would have expected to identify this. Thus, basing starting dose on individual MED assessments may not influence the treatment's efficacy in a skin phototype I to III population, although it remains important for patient safety. It remains possible that in populations containing individuals with a broader range of erythemal sensitivity, basing the starting dose on MED testing could have an important impact on treatment effectiveness. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN84614024.

UV-B phototherapy clears psoriasis through local effects.

OBJECTIVE: To determine if UV-B phototherapy clears psoriasis through systemic effects. DESIGN: Randomized, within-subject comparison of change in psoriasis in 3 plaques in patients attending for whole-body UV-B therapy. Change in patients' psoriasis plaques covered during UV-B treatment was compared with plaques in an untreated control group. SETTING: University hospital phototherapy unit. PATIENTS: The study population comprised 17 patients with chronic plaque psoriasis treated with UV-B and 24 psoriasis control patients awaiting UV-B phototherapy. INTERVENTIONS: Treatment with a standard 3-times weekly narrowband TL-01 UV-B regimen. Three similar plaques were randomly allocated to be covered every treatment, covered for 2 of 3 weekly treatments, and exposed to local UV-B every treatment. Similar plaques were selected in control patients (awaiting but not yet started UV-B therapy). Severity of psoriasis plaques was assessed using a scaling, erythema, and induration (SEI) scoring system. MAIN OUTCOME MEASURES: Change in SEI score of the selected plaques over the complete treatment course for UV-B-treated patients and change over 3 weeks in SEI score of plaques covered during UV-B treatment compared with that of plaques in controls. RESULTS: There was a significant (P<.001) difference in how much the SEI score changed in the 3 plaques in UV-B-treated patients. It fell by a mean of 7.6 for uncovered plaques compared with 3.2 for plaques covered during each UV-B exposure (95% confidence interval for difference, 3.0 to 5.8). In patients awaiting UV-B, SEI score of plaques fell by a mean of 0.4 over 3 weeks, compared with a mean fall of 1.4 for covered plaques in UV-B-treated patients (95% confidence interval for difference in means, 0.1 to 2.0). CONCLUSIONS: If UV-B therapy has any systemic effect capable of improving psoriasis, this effect is small and unlikely to be of clinical importance. It is insufficient to alter interpretation of findings of within-subject comparative phototherapy studies. UV-B phototherapy works for chronic plaque psoriasis through local effects.