ABSTRACT
The U.S. Food and Drug Administration (FDA) issued guidance on requirements to assess cardiovascular disease (CVD) risk with drugs being developed for approval for clinical use. The guidance was triggered by a meta-analysis published by Nissen and Wolski that suggested an increased risk for myocardial infarction with the use of rosiglitazone. This article discusses controversies around CVD trials in diabetes beginning with the University Group Diabetes Program. This is followed by a brief description of the FDA guidance for evaluating CVD risk with glucose-lowering medications. Limitations of meta-analyses of data from phase 2 and 3 (phase 2/3) trials to inform CVD risk are highlighted. These include the differences between patient characteristics in phase 2/3 trials and those in cardiovascular outcome trials (CVOTs) and the relatively short exposure time in phase 2/3 trials. The differences may partly explain the observed disparity between phase 2/3 meta-analyses and the results of completed CVOTs. Approaches to understanding CVD risk with a new medication should get to the answer about risk as efficiently as possible to minimize any potential harm to patients. In that context, we discuss options for clinical trial design and an alternative approach for statistical analyses.
Subject(s)
Cardiovascular Diseases/chemically induced , Diabetes Mellitus/drug therapy , Drug Discovery , Drug Evaluation, Preclinical , Hypoglycemic Agents/adverse effects , Cardiovascular Diseases/epidemiology , Drug Discovery/methods , Drug Discovery/standards , Drug Evaluation, Preclinical/methods , Drug Evaluation, Preclinical/standards , Drug Industry/trends , Humans , Hypoglycemic Agents/therapeutic use , Myocardial Infarction/chemically induced , Risk Assessment , Rosiglitazone , Thiazolidinediones/therapeutic use , United States , United States Food and Drug AdministrationABSTRACT
BACKGROUND: Because insulin dosing requires optimization of glycemic control, it is important to use a single metric of benefit and risk to determine best insulin dosing practices. We retrospectively applied a multiplicative clinical utility index (CUI) to a study of LY2605541 (Eli Lilly and Company, Indianapolis, IN), a novel, long-acting basal insulin. MATERIALS AND METHODS: A CUI was developed to transform the multidimensional problem of assessing benefit/risk of multiple dosing algorithms into a single decision-making metric to evaluate two LY2605541 dosing algorithms relative to the insulin glargine (GL) dosing algorithm. The CUI was applied to data in a 12-week, open-label, Phase 2 trial in patients with type 2 diabetes mellitus who were randomized to one of two dosing algorithms for LY2605541 (LY1 or LY2) or GL (algorithm similar to LY1). The CUI was created (via expert input) by weighing the relative benefit/risk of four components (glycosylated hemoglobin [HbA1c], percentage of patients with HbA1c ≤ 7%, hypoglycemia rate, and time to steady-state dose); individual utility values were multiplied to compute CUI values for LY1 and LY2 relative to GL, and bootstrap samples were used to determine variability. RESULTS: The mean CUI was 0.82 for LY1 and 1.35 for LY2. Based on 3,000 bootstrap samples, there was a 48% probability of LY2 performing better than LY1 and a 28% probability of LY1 performing better than LY2. CONCLUSIONS: CUI methodology, and in particular this CUI, is a useful tool for comparing dosing algorithms. Based on this CUI, LY2 is likely to be a better dosing algorithm than LY1.
Subject(s)
Blood Glucose/drug effects , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemia/prevention & control , Hypoglycemic Agents/administration & dosage , Insulin Lispro/administration & dosage , Insulin, Long-Acting/administration & dosage , Polyethylene Glycols/administration & dosage , Algorithms , Blood Glucose/metabolism , Clinical Trials, Phase II as Topic , Decision Making , Diabetes Mellitus, Type 2/blood , Drug Administration Schedule , Female , Humans , Hypoglycemia/chemically induced , Hypoglycemic Agents/adverse effects , Insulin Glargine , Insulin Lispro/adverse effects , Male , Middle Aged , Polyethylene Glycols/adverse effects , Retrospective Studies , Risk Assessment , Treatment OutcomeABSTRACT
Participants in early Phase I clinical trials for drugs designed to enhance cognition are typically healthy volunteers. If improvement can be detected with a battery of cognitive tests in healthy volunteers, such a battery could be a pharmacodynamic marker in the future development of the compound for treatment of cognitive disorders. In the present exploratory study, a battery of neuropsychological (NP) tests was used to determine if changes in cognition from a pharmacological intervention could be detected in healthy volunteers. A drug with known cognitive-enhancing effects in Alzheimer's disease, donepezil, was compared with placebo and no treatment arms. Carry-over effects of repeated test administration were also assessed. In this double-blind study, 27 healthy adults were randomized into one of three arms (eight donepezil, nine placebo and 10 no treatment) and completed 14 days of donepezil (5 mg q.h.s.) or placebo (q.h.s.). A battery of NP tests was administered on days 0, 7, 14 (randomization), 21, 28 (end of treatment) and 42 (washout). There were no differences in performance between the placebo and the no treatment arms. However, on day 21, subjects in the donepezil group performed slightly but significantly worse on some tests of speed, attention and memory (p < 0.05) compared to the pooled control group (placebo and no treatment arms). No improvement in performance was present while on donepezil at days 21 or 28. While the results are counter to expectations, some tests in the battery did detect a cognitive change (transient mild worsening during drug administration) in healthy volunteers.
