How to ascertain drug safety in the context of benefit. Controversies and concerns.

There is great concern about clearly defining benefit and risk in the context of both drug development and clinical practice. In view of this pressure, the OMERACT Executive identified the need to bring together clinical trialists, pharmacoepidemiologists, clinicians, clinical epidemiologists, statistical experts, and regulatory representatives to discuss different approaches to define risk and perhaps improved ways to express it. Each attendee spoke on a given topic and the group was charged to consider the issue of risk in the context of formally posed questions. This article provides a summary of the presentations and outlines the discussions that followed.

Evidence for endoscopic ulcers as meaningful surrogate endpoint for clinically significant upper gastrointestinal harm.

BACKGROUND & AIMS: Surrogate endpoints are biomarkers intended to substitute for a clinical endpoint. Are endoscopic ulcers a useful surrogate endpoint for a biological progression to clinical endpoints of ulcer complications (perforation, ulcers, and bleeds), hospital admission, or death? METHODS: Review of randomized trials, meta-analyses, clinical outcomes trials, and observational studies. RESULTS: No large study examined both endoscopic and clinical endpoints. Endoscopic ulcers and clinically significant ulcer complications were affected in the same direction and to about the same extent in 4 distinct circumstances: (1) by risk factors-age, previous history of symptomatic ulcer or bleeding, Helicobacter pylori, aspirin; (2) in studies of antiulcer treatments with differing modes of action, especially in relation to nonsteroidal anti-inflammatory drug toxicity, and Helicobacter pylori infection; (3) in studies evaluating ulcer complications with Cox-2 selective drugs and nonsteroidal anti-inflammatory drugs; and (4) in studies of interventions in patients with high risk of recurrent ulcer bleed needing nonsteroidal anti-inflammatory drug therapy. All study designs showed consistent and reproducible effects on gastrointestinal ulcer complications paralleling endoscopy. CONCLUSIONS: Consistent and plausible findings from disparate populations and designs make endoscopic ulcers a strong candidate for surrogacy, though direct progression from endoscopic ulcers to ulcer complications cannot be demonstrated. Large outcome studies are needed to establish the power of the surrogacy, absolute risk of clinical outcomes, and to identify the totality of risks and benefits of new pharmacologic therapies.