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Patients of gastroesophageal reflux disease (GERD) that have been frequently diagnosed, or misdiagnosed, have been dissatisfied with the available treatment. To resolve this issue, industry players must define meaningful endpoints for future trials, incorporate patient reported outcomes, and apply biomarkers.
By Colin W. Howden, MD, AGAF, division chief of the University of Tennessee Health Sciences Center and chair of the scientific advisory board for the American Gastroenterological Association (AGA) Center for Diagnostics and Therapeutics. Dr. Howden will serve as co-chair of the 2016 AGA Drug Development Conference.
This article is part of a series on drug development in gastroenterology from members of the American Gastroenterological Association Center for Diagnostics and Therapeutics.
If you’re interested in learning more about drug development in this area, join the center for its first Drug Development Conference, Oct. 27-28, 2016, in Washington, DC.
In the early 1990s, there was much optimism concerning the treatment of
gastroesophageal reflux disease, or GERD
. Omeprazole, the prototypical proton pump inhibitor (PPI), had just been approved. My clinics seemed full of patients with GERD symptoms that were inadequately managed by H
-receptor antagonists (H
RAs), which they were sometimes taking in excessive doses. My line of action was straightforward; for many of these patients, an upgrade to PPI treatment was the obvious strategy - and the vast majority appeared to be satisfied with the results. Now, things are much less clear. Gastroenterologists across the U.S. frequently see patients diagnosed, or misdiagnosed, with GERD and are dissatisfied with PPI treatment. (Unfortunately, those patients are sometimes given the unintentionally derogatory label of “PPI failures” - a term whose application I have never encouraged.) As in the early 1990s with high-dose H
RA treatment, many patients now express dissatisfaction with higher-than-approved doses of a PPI. Some are supplementing a prescription PPI with an over-the-counter version of the same or a different PPI, some with an H
RA, while some continue to suffer in relative silence. How did this go wrong? Have we set patients’ expectations of PPI treatment too high? Have we focused too much on suppression of gastric acidity in attempting to treat a condition that is essentially based on disordered gastrointestinal motility? Regrettably, in registration clinical trials, our original focus was on an endpoint that was of little practical clinical utility - namely the endoscopically-demonstrated healing of erosive esophagitis after an arbitrary eight-week treatment period. Instead, we should have been focusing on more clinically relevant outcomes such as level of symptom control and patients’ quality-of-life measures. With the introduction of subsequent PPIs to the market, increasing attention was placed on very minor alleged or imputed differences between competing agents in, for example, their rapidity of onset of action, ability to better control nighttime symptoms, perceived lack of a “food effect” and relative safety and tolerability profiles taking into account such often nebulous issues as drug-drug interactions. Attempts to regulate the disturbances in gastrointestinal motility that underlie GERD have, to date, been met with failure. Drugs that had been developed to modulate lower esophageal sphincter relaxations through various mechanisms have had their development discontinued because of failure to demonstrate adequate efficacy. However, perhaps some of the clinical trials may have suffered from the recruitment of patients who were less likely to respond to such an approach. While it is difficult to envisage a motility-modifying drug out-performing a PPI in patients with erosive esophagitis, such agents could benefit selected patients with non-erosive reflux disease (NERD) and a symptom profile that extends beyond heartburn. However, clinical trials in patients with presumed NERD have been adversely affected by the inclusion of patients whose symptoms were, often in retrospect, largely functional in nature. Given the observation that many patients with the diagnosis of GERD are unhappy with PPI treatment and the increasing recognition that PPIs treat heartburn better than other GERD-related symptoms, there is clearly room for improvement. We need to remember that neither P in PPI stands for panacea. It’s not a simple issue. We need to define meaningful endpoints for future clinical trials, the optimal incorporation of patient reported outcomes, and the application of biomarkers. This will take collaboration between physicians and researchers, pharma, and FDA, which is exactly why the
American Gastroenterological Association
Center for Diagnostics and Therapeutics
, of which I serve as chair of the advisory board. I’m optimistic that our work and collaboration with thought leaders across the drug development space will lead to improved treatments for our patients suffering from GI conditions such as GERD.