Skip links

Endpoint for GI Toxicity Clarified

NSAIDs are known to induce gastrointestinal (GI) tract toxicity, notably upper GI tract. Drugs that suppress gastric acid secretion such as histamine type 2 receptor antagonists, proton pump inhibitors (PPIs), NSAIDs (e.g., COX-2 selective drugs), and misoprostol (a prostaglandin E analog that also has mucosal protective properties) have been studied for their ability to protect the GI tract in patients taking NSAIDs. However, determining the efficacy endpoints for such drugs in reducing GI toxicity has been a tough task for FDA so far. The Division of Gastroenterology Products (DGP) has used endoscopically proven ulcers as the surrogate endpoint* to approve several products for the indication of risk reduction of NSAID-associated upper GI toxicity (the latest drug approved is VimovoÃ’ by AstraZeneca LP, 04/30/2010). Whereas the Division of Anesthesia and Analgesia Products (DAAP) has required clinical outcome trials to demonstrate a reduction in upper GI complications (UGICs), such as perforations, obstructions, and bleeding. * ( A surrogate endpoint is defined as a laboratory measure or marker or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and is expected to predict the effect of the therapy.

To address these differences within the Agency, the 2 divisions met and examined the basis for the different approaches. After performing a review of cross-study comparisons of ulcers in endoscopy trials to UGICs in outcome trials of three product classes, a consensus was reached that the endoscopically demonstrated ulcers correlate with UGICs.

In the GDAC meeting (11/04/2010), the panel voted 8-4 (1 member abstaining), that the surrogate endpoint (endoscopically observed ulcers) could serve as an adequate primary efficacy endpoint for evaluating existing drugs. However, the same doesn’t hold true for drugs not yet on market (novel investigative products with new mechanisms of action) (voted 4-8 with 1 member abstaining).

The same panel met the following day to discuss the role of PPIs in infants with gastroesophageal reflux disease (GERD). The meeting was conducted in response to a request by manufacturers under the Best Pharmaceuticals for Children Act (Nexium®, esomeprazole by AstraZeneca LP; Prevacid®, lansoprazole by Takeda Pharmaceuticals North America, Inc; Protonix®, pantoprazole by Pfizer, Inc.) and PREA commitment (Prilosec®. omeprazole by AstraZeneca LP).  None of these 4 PPIs has been approved for use in infants.

The panel didn’t officially vote, but it agreed that studies in infants with GERD should be required for PPIs before they are approved for symptomatic GERD in adults. The response to the question “Is the pathophysiology of GERD the same in patients ages 1 month to less than 1 year and adults?” was a categorical ‘no’ by panelist Alexander Rakowsky, MD (Nationwide Children’s Hospital, Columbus, Ohio).

Camargo’s Shouryadeep Srivastava, MBBS, PhD contributed this post.