Dose-finding studies in drug development for rare genetic diseases.

BACKGROUND: The small patient populations inherent to rare genetic diseases present many challenges to the traditional drug development paradigm. One major challenge is generating sufficient data in early phase studies to inform dose selection for later phase studies and dose optimization for clinical use of the drug. However, optimizing the benefit-risk profile of drugs through appropriate dose selection during drug development is critical for all drugs, including those being developed to treat rare diseases. Recognizing the challenges of conducting dose finding studies in rare disease populations and the importance of dose selection and optimization for successful drug development, we assessed the dose-finding studies and analyses conducted for drugs recently approved for rare genetic diseases. RESULTS: Of the 40 marketing applications for new molecular entity (NME) drugs and biologics approved by the United States Food and Drug Administration for rare genetic diseases from 2015 to 2020, 21 (53%) of the development programs conducted at least one dedicated dose-finding study. In addition, the majority of drug development programs conducted clinical studies in healthy subjects and included population pharmacokinetic and exposure-response analyses; some programs also conducted clinical studies in patient populations other than the disease for which the drug was initially approved. The majority of primary endpoints utilized in dedicated dose-finding studies were biomarkers, and the primary endpoint of the safety and efficacy study matched the primary endpoint used in the dose finding study in 9 of 13 (69%) drug development programs where primary study endpoints were assessed. CONCLUSIONS: Our study showed that NME drug development programs for rare genetic diseases utilize multiple data sources for dosing information, including studies in healthy subjects, population pharmacokinetic analyses, and exposure-response analyses. In addition, our results indicate that biomarkers play a key role in dose-finding studies for rare genetic disease drug development programs. Our findings highlight the need to develop study designs and methods to allow adequate dose-finding efforts within rare disease drug development programs that help overcome the challenges presented by low patient prevalence and other factors. Furthermore, the frequent reliance on biomarkers as endpoints for dose-finding studies underscores the importance of biomarker development in rare diseases.

Informal and formal support among community-dwelling Japanese American elders living alone in Chicagoland: an in-depth qualitative study.

A key public health approach to promote independent living and avoid nursing home placement is ensuring that elders can obtain adequate informal support from family and friends, as well as formal support from community services. This study aims to describe the use of informal and formal support among community-dwelling Nikkei elders living alone, and explore perceived barriers hindering their use of such support. We conducted English and Japanese semi-structured, open-ended interviews in Chicagoland with a convenience sample of 34 Nikkei elders age 60+ who were functionally independent and living alone; 9 family/friends; and 10 local service providers. According to participants, for informal support, Nikkei elders relied mainly on: family for homemaking and health management; partners for emotional and emergency support; friends for emotional and transportation support; and neighbors for emergency assistance. Perceived barriers to informal support included elders' attitudinal impediments (feeling burdensome, reciprocating support, self-reliance), family-related interpersonal circumstances (poor communication, distance, intergenerational differences); and friendship/neighbor-related interpersonal situations (difficulty making friends, relocation, health decline/death). For formal support, Nikkei elders primarily used adult day care/cultural programs for socializing and learning and in-home care for personal/homemaking assistance and companionship. Barriers to formal support included attitudinal impediments (stoicism, privacy, frugality); perception of care (incompatibility with services, poor opinions of in-home care quality); and accessibility (geographical distance, lack of transportation). In summary, this study provides important preliminary insights for future community strategies that will target resources and training for support networks of Nikkei elders living alone to maximize their likelihood to age in place independently.

A comparison of rapid and conventional measures of indicator bacteria as predictors of waterborne protozoan pathogen presence and density.

E. coli and enterococci in recreational waters are monitored as indicators of fecal contamination, pathogen presence, and health risk. Quantitative polymerase chain reaction (qPCR) tests for fecal indicator bacteria can provide beach managers with same-day information about water quality, unlike culture methods which provide that information the following day. The abilities of qPCR measurements of indicator bacteria, as compared to culture measurements of indicator bacteria, as predictors of pathogen presence or density in surface waters are not well understood. The purpose of this study was to make such comparisons between water samples collected from Chicago area surface waters, including rivers, inland lakes, Lake Michigan, and the Chicago Area Waterways System, which is dominated by wastewater effluent. A total of 294 twenty-litre samples were collected and analyzed for Giardia and Cryptosporidium. qPCR and membrane filtration methods were used to quantify E. coli and enterococci. Correlation, logistic regression, and zero-inflated Poisson modeling were utilized to evaluate associations between indicators and parasites. qPCR and culture measures of the indicator bacteria were similar in their ability to predict parasite presence and density. Correlations between parasites and indicators were generally stronger at waters not dominated by effluent. Associations between indicator density and Giarida presence were observed more consistently than between indicator density and Cryptosporidium presence. Associations between enterococci and parasites were generally stronger than associations between E. coli and parasites. The use of qPCR monitoring in our setting would generate more timely results without compromising the ability to predict parasite presence or density.