AGA continuously engages with FDA to understand their decisions impacting gastroenterology. Here are meeting summaries from two FDA presentations on new drug approvals in GI and controversies around measuring drug toxicity.
What is covered: Four presentations from the FDA addressing the rationale and considerations behind key product approvals for GI indications during 2018 and the first half of 2019.
- Tegaserod for treatment of irritable bowel syndrome with constipation (IBS-C) in adult women < 65 years of age. Tegaserod was pulled from the U.S. market in 2007 when cardiovascular (CV) ischemic events were identified as a potential safety signal. Upon analysis of new safety data including 29 randomized, placebo-controlled trials and seven open-label trials, an advisory committee of the FDA agreed that the CV safety signal was weak and that the benefits outweighed potential risks for women who were at low CV risk. In addition, a signal was also identified for suicidal ideation or behavior, which although weak, was incorporated into the product label.
- Prucalopride for treatment of chronic idiopathic constipation in adults. Because prucalopride and tegaserod are both 5-HT4 agonists, risks of CV events and suicidal ideation/behavior were of similar concerns during the assessment of prucalopride. It was determined that there was no difference in CV risk between placebo and prucalopride, but that there was still a concern for possible risk of suicidal ideation/behavior, which was incorporated into the product label.
- Tofacitinib for the treatment of moderate-to-severe ulcerative colitis in adults. Originally approved for rheumatoid arthritis in 2012 at a dose of 5 mg two times per day (BID), the FDA exercised scientific judgment to determine if data from an uncontrolled, open-label extension study using 10 mg BID could be used to support labeling for an extended induction as an alternative dosing regimen. It was unusual to use uncontrolled, open-label data for product labeling, but it was determined that in specific situations, such as patients who may require more time to respond to induction therapy, the data supported the use of tofacitinib dosing past eight weeks but no more than 16 weeks.
- Fish oil triglycerides as a source of calories and fatty acids in pediatric patients with parental nutrition-associated cholestasis (PNAC). The approval of fish oil triglycerides involved a unique regulatory approach using historical controls who had received the therapy through an expanded access program in the U.S. Based on the data available, the proposed indication of treatment of PNAC was ultimately changed to providing the product as an effective and safe source of nutrition in patients with PNAC. Post-approval studies are being conducted to assess long-term safety, as the essential fatty acid in fish oils have been associated with prolonged bleeding and neurodevelopment delays.
Another FDA Town Hall will be held at Digestive Disease Week® 2020. It is currently scheduled for Monday, May 4, at 2 p.m.
What is covered: Perspectives of gastroenterologists and FDA officials on serotonin type 3 (5-HT3) antagonists, serotonin type 4 (5-HT4) agonists and proton pump inhibitors (PPIs), classes of drugs that as noted above have been associated with safety concerns.
- 5HT3 antagonists, 5-HT4 agonists: The only 5-HT3 antagonist that is currently FDA-approved for irritable bowel syndrome with diarrhea (IBS-D) is alosetron. Although this was pulled from the market in 2000, it was subsequently re-introduced with specific restrictions on its use confining it to women with severe IBS-D unresponsive to other treatments. There has been more progress with the 5-HT4 agonists with the recent reintroduction of tegaserod and the approval of prucalopride, although these products are for IBS-C. It was noted that prucalopride seems to lack the side effects seen with other drugs in its class. FDA noted that continued surveillance of safety after product approval is critical to make informed decisions on risk for adverse events.
- PPIs: PPIs have been associated in uncontrolled, observational studies with various side effects ranging from pneumonia to dementia. This may be because, on average, sicker patients who may be more susceptible to other illnesses are prescribed PPIs. A large randomized, controlled trial involving over 17,000 participants was recently reported and showed no harms from PPIs compared to placebo apart from a possible increased risk of gastrointestinal infections. The FDA discussed PPIs and bone fractures as an example of how the agency uses non-randomized studies of an intervention (NRSI) to inform regulatory decisions. Although the FDA ultimately communicated the evidence for an association between fracture and use of PPIs at a high dose or for a long duration, the agency also publicly noted that it was unclear whether the use of PPIs was the cause of this side effect.