A Phase One Safety Study of Lactobacillus reuteri Conducted in the Peruvian Amazon: Observations from the Field

Abstract

Abstract. Clinical research on probiotics presents challenging issues for researchers, regulators, and funding agencies, and these issues become more complex when United States federally funded research is conducted outside the United States. Here, we describe the design and results of a Phase I safety study of Lactobacillus reuteri DSM 17938 conducted as a community-based trial under the Food and Drug Administration Investigative New Drug (FDA IND) program in a small town in the Peruvian Amazon. Forty-five healthy adults 18 to 65 years of age were randomized in a 2:1 ratio to receive either Lactobacillus reuteri 10 8 organisms once daily for 5 days or an identical appearing placebo. Results showed no evidence of invasive infection resulting from probiotic administration and no differences between groups. Although we encountered several challenges in conducting an FDA-approved safety trial in this setting, the rigorously collected contextually relevant data will be very valuable to support later Phase II/III studies of L. reuteri for use in similar settings.Probiotic products, including nutritional supplements and preparations designed to provide health benefits, have generated increased attention from both the biomedical community and the lay press during the last 10 years, as consumers in many countries are eager for alternative, natural, and cost-effective ways to improve health and prevent or treat diseases. [1][2][3][4] "Probiotics" are intended to contain non-pathogenic microorganisms generally administered orally to colonize the gastrointestinal tract, where they have the potential to improve health through modulating the microbiome. Human microbiome research has rekindled interest in probiotics, 5-8 as the structure of the microbiome is linked with metabolic phenotypes in the host, and thus the use of select probiotic organisms to orchestrate beneficial changes is gaining scientific support. 9 Clinical research on probiotics for prevention or treatment of human diseases, such as infectious diarrhea, presents new and challenging questions and issues for researchers, regulatory agencies, and funding agencies 10,11 ; most probiotic products are produced by food manufacturers and marketed as nutritional supplements, without claiming any specific health benefits. The U.S. Food and Drug Administration also categorized some of these probiotic preparations as "Generally Regarded as Safe or GRAS" products. The use of probiotics is broad in the extreme, and they are present in yogurt, beverages, dietary supplements, and animal feed in an increasing number of countries. However, when investigators in the United States evaluate the therapeutic effect of probiotics or any other products to treat, mitigate, prevent, or cure disease states, United States regulations determine that they are being used as pharmaceuticals for a medical indication, and regulates them accordingly. Pharmaceutical products to be used for medical indications are produced and controlled in a far more stringent way than food products and dietary...

Safety and acceptability of Lactobacillus reuteri DSM 17938 and Bifidobacterium longum subspecies infantis 35624 in Bangladeshi infants: a phase I randomized clinical trial

“…The choice of probiotics in this study was based on a literature review and strong safety data in infants. Lactobacillus reuteri DSM 17938 (parent strain L. reuteri ATCC 55730) [ 9 ] has been safely used in infants [ 10 ] and adults in the US and Europe [ 11 ] and recently in adults in the Peruvian Amazon [ 12 ] and has been reported to prevent or reduce diarrhea and gastrointestinal and respiratory infections [ 13 – 15 ], reduce pathogen colonization and alter microbiota composition [ 16 , 17 ], reduce infant colic and crying time [ 18 – 20 ], suppress Helicobacter pylori and gastric symptoms [ 21 ], relieve constipation [ 22 ], control reflux and abdominal pain [ 23 ], and improve infant weight gain [ 24 ]. Bifidobacterium longum subspecies infantis is commonly found in both breast milk [ 25 ] and healthy infant stools [ 4 ] and is generally recognized as safe [ 26 ].…”