RESUMEN
INTRODUCTION: It is widely believed that acceptable bioequivalence studies of drugs with high within-subject pharmacokinetic variability must enroll higher numbers of subjects than studies of drugs with lower variability. We studied the scope of this issue within US generic drug regulatory submissions. MATERIALS AND METHODS: We collected data from all in vivo bioequivalence studies reviewed at FDA's Office of Generic Drugs (OGD) from 2003-2005. We used the ANOVA root mean square error (RMSE) from bioequivalence statistical analyses to estimate within-subject variability. A drug was considered highly variable if its RMSE for C (max) and/or AUC was > or =0.3. To identify factors contributing to high variability, we evaluated drug substance pharmacokinetic characteristics and drug product dissolution performance. RESULTS AND DISCUSSION: In 2003-2005, the OGD reviewed 1,010 acceptable bioequivalence studies of 180 different drugs, of which 31% (57/180) were highly variable. Of these highly variable drugs, 51%, 10%, and 39% were either consistently, borderline, or inconsistently highly variable, respectively. We observed that most of the consistent and borderline highly variable drugs underwent extensive first pass metabolism. Drug product dissolution variability was high for about half of the inconsistently highly variable drugs. We could not identify factors causing variability for the other half. Studies of highly variable drugs generally used more subjects than studies of lower variability drugs. CONCLUSION: About 60% of the highly variable drugs we surveyed were highly variable due to drug substance pharmacokinetic characteristics. For about 20% of the highly variable drugs, it appeared that formulation performance contributed to the high variability.
Asunto(s)
Aprobación de Drogas/métodos , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/normas , United States Food and Drug Administration , Ensayos Clínicos como Asunto/métodos , Ensayos Clínicos como Asunto/normas , Humanos , Equivalencia Terapéutica , Estados UnidosRESUMEN
BACKGROUND: Very little is known about the natural history of challenging behaviour and psychiatric disorder in people with severe and profound degrees of intellectual disability. AIMS: To clarify the natural history of challenging behaviour and psychiatric disorder in this population through a longterm prospective cohort study over a 26-year period. METHOD: One hundred individuals with severe or profound intellectual disability were randomly selected in 1975. Their behaviour was recorded through carer and psychiatrist ratings using the Modified Manifest Abnormality Scale of the Clinical Interview Schedule. The presence and severity of psychiatric disorder were also recorded. The study was repeated in 1981/82 and 1992/93. We repeated the study again in 2001, supplementing the original observational data with the Checklist of Challenging Behaviour. RESULTS: Behavioural symptomatology is remarkably persistent, particularly stereotypy, emotional abnormalities, eye avoidance and overactivity, although the severity of overall psychiatric disorder does show some abatement through time. CONCLUSIONS: These findings influence the prospects of success in relocating adults with severe and profound degrees of intellectual disability back into the community.