This article concerns development and use of patient-reported outcomes (PROs) in clinical trials to evaluate medical products. A PRO is any report coming directly from patients, without interpretation by physicians or others, about how they function or feel in relation to a health condition and its therapy. PRO instruments are used to measure these patient reports. PROs provide a unique perspective on medical therapy, because some effects of a health condition and its therapy are known only to patients. Properly developed and evaluated PRO instruments also have the potential to provide more sensitive and specific measurements of the effects of medical therapies, thereby increasing the efficiency of clinical trials that attempt to measure the meaningful treatment benefits of those therapies. Poorly developed and evaluated instruments may provide misleading conclusions or data that cannot be used to support product labeling claims. We review selected major challenges from Food and Drug Administration's perspective in using PRO instruments, measures, and end points to support treatment benefit claims in product labeling. These challenges highlight the need for sponsors to formulate desired labeling claim(s) prospectively, to acquire and document information needed to support these claim(s), and to identify existing instruments or develop new and more appropriate PRO instruments for evaluating treatment benefit in the defined population in which they will seek claims.

SummaryThe frequency of mutant T cells (FMC) in blood lymphocytes from patients with systemic hpus erythematosus (SLE) was measured by growing cells in the presence and in the absence of 6-thioguanine. Patients with SLE had a spectrum of FMC ranging from normal to about 100 times normal. This high FMC among calls from SLE patients appears to reflect excessive in vivo activation and proliferation during the course of the disease. This represents the first demonstration of such a T cell abnormality in SLE; it supports the hypothesis that SLE T cells demonstrate increased in vivo division and/or survival.

Objective. To determine the clinical features that contribute to an increased frequency of mutant T cells (FMC) in patients with systemic lupus erythematosus (SLE).Methods. During in vivo T cell division, there are errors in replication which give rise to mutations throughout the genome. An estimate of such mutations may be obtained by focusing on mutations in the hprt gene, which can be screened by assessing relative growth of T cell clones in the presence and absence of 6-thioguanine. In this study, peripheral blood T cell clones from 47 patients with SLE were assessed, and the frequency of mutant T cells (FMC) determined. An attempt was made to correlate the FMC with disease measures.Results. Patients with SLE had a spectrum of FMC values, ranging from normal to almost 1,000 times normal. Total duration of active disease (r, = 0.94), past highest disease activity index (r, = 0.80), and number of lupus flares (r, = 0.76) correlated most strongly (P < 0.0001) with FMC by Spearman's rank order analysis. In contrast, current disease activity index and current anti-DNA level did not correlate with FMC. Similar correlations between FMC I and cumulative past lupus disease activity were found by linear regression analysis (rp = 0.89 for the correlation between the natural From the Arthritis and Rheumatism Branch, NIAMS, NIH,

The morphology, distribution and quantitation of dendritic (Langerhans) cells (LC) was determined by analysis of ADPase stained epithelial flat mounts from 6-8 week young adult (resistant) and 24 month old (susceptible) aged mice before and after experimental infection with P. aeruginosa topically applied to the scarified cornea. The contralateral eye (controls) was also scarified and phosphate buffered saline applied similarly. This study has examined the changes in ADPase positive cell populations of the conjunctival limbal epithelium and corneal epithelium of naturally resistant mice (Swiss-Webster and CD2F1) following corneal infection with Pseudomonas aeruginosa at two different ages, young adult (8 week old) and aged (24 month old). The young adult mice recover from their infection and restore corneal clarity while the aged mice have extensive ocular destruction and corneal scarring. Conjunctival limbal dendritic cell numbers in young adult mice were found to be significantly increased at day seven post infection and then returned to baseline levels. In contrast, conjunctival limbal dendritic cell numbers in aged mice were found to increase slowly and to peak at fourteen days after infection. Other differences between the two ages (young adult and aged) included an initial increase in dendritic cells five hours post infection in the young adult groups and an initial decrease at five hours in the aged groups of mice.