Drug safety monitoring is a complex and multifaceted practice, in which both physicians and the US Food and Drug Administration (FDA) must work in concert to ensure the safety of drugs used in clinical practice.1

At Digestive Disease Week 2019, the American Gastroenterological Association’s Clinical Practice Center, in conjunction with both the Division of Gastroenterology and Inborn Errors Products at the Center for Drug Evaluation and Research and the FDA, cosponsored a symposium focused on “assessing and monitoring toxicity of medicines used in gastrointestinal (GI) disorders.” A report of the proceedings, published in Gastroenterology, is the third article in a series centered on the core aspects of GI drug development.1

‘This report details some of the activities and responsibilities of the FDA, and some clinical perspectives on [proton pump inhibitors (PPIs)] and serotonergic agents,” wrote report author Colin W. Howden, MD.1 “Its aim is to promote an interchange of ideas among pharmaceutical companies, clinicians, and regulators in order to advance the development and utilization of new therapies for GI disorders.”


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The Role of the FDA: Overview

“As a matter of general process, the FDA evaluates the benefits and risks for the population, the provider for the patient, and the patient for himself/herself, specifically in the context of his [or] her own personal values,” said Joyce Korvick, MD, MPH, of the Division of Gastroenterology and Inborn Errors Products at the FDA, in her overview of the drug safety evaluation process.1 Per the 21st Century Cures Act, the pre- and postmarket drug lifecycle is particularly focused on the balance of benefits and risks, based on real-world evidence and real-world data.

“Benefit/risk assessments are completed for products throughout their lifecycle, from development through approval and into the postmarketing setting,” she added.1

All drugs must undergo a safety evaluation based on information provided in the New Drug Application or Biologics License Application, Dr Korvick noted.1 Safety data must be collected from well-controlled clinical trials, conducted within specific patient populations treating specific diseases.

Dr Korvick also highlighted the FDA Adverse Events Reporting System (FAERS), which — in conjunction with observational studies, medical literature, and the FDA’s Sentinel System — is used to conduct postapproval pharmacovigilance assessments.

“The determination of whether there is a causal association between a product and an adverse event is based upon the strength of evidence from the totality of data for the product review,” Dr Korvick said.1

Despite the numerous systems in place, challenges still exist in evaluating the benefit of therapeutic products for GI conditions. These challenges include small efficacy margins, large placebo effects, and evolving outcome measures, typically reliant on patient reported outcomes instead of objective disease measures. It is particularly challenging in studies of pediatric populations due to issues with quantifying disease severity compared with adults.

Additional challenges exist surrounding chronic GI diseases, including the complexities of chronic administration, treatment switching, disease impact over time, limited prevalence of certain conditions, small clinical trial size, and study design issues.1

The Role of the FDA: Surveillance

Lisa Harinstein, MD, of the Division of Pharmacovigilance, the Office of Surveillance and Epidemiology, and the Center for Drug Evaluation and Research at the FDA, then discussed the role of postmarketing safety surveillance to both identify and refine safety signals for drugs and biologic products.

“Postmarketing safety surveillance is critical because of differences in how and in whom the product is to be used in the real-world setting as compared to preapproval clinical trials,” Dr Harinstein noted.1 The FAERS database, for example, is intended to identify safety issues and specifically support the FDA’s current postmarketing safety surveillance program for both drugs and biologics. FAERS, she noted, contains “[adverse event] reports, medication error reports and product quality complaints resulting in [adverse events] submitted to the FDA.”1 As of May 2019, FAERS contained approximately 18 million reports.”1

Adverse events reported via FAERS are then reviewed and interpreted by safety evaluators with the FDA’s Office of Surveillance and Epidemiology. Although the presence of a FAERS report does not establish a causal relationship between the product and the adverse event, further analysis is conducted to identify potential case series and other data sources such as medical literature, clinical trial data, and public health databases.1

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Examples of Real-World Safety Issues

Two recent safety issues in current GI drugs were presented to highlight the importance and impact of postmarketing safety surveillance: serious cardiac adverse events associated with higher-than-recommended doses of loperamide, and serious pancreatitis in patients without a gallbladder who received eluxadoline.

Both safety issues were identified through reports made to the FAERS database,2,3 and both reports resulted in the publication of Drug Safety Communications and labeling updates.

As a result of these reports, by January 2018, FDA manufacturer efforts to restrict over-the-counter loperamide packaging were underway, and the FDA performed a 1-year reassessment of pancreatitis cases with eluxadoline therapy.1

“These 2 examples underscore the importance of continued surveillance of postmarketing safety issues to make informed decisions on risk,” Dr Howden noted.1