S137.full, ARTYKUŁY NAUKOWE (probiotyki, mikroflora, germ-free)
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//-->SUPPLEMENT ARTICLEProbiotic Foods and Drugs: Impact of US RegulatoryStatus on Design of Clinical TrialsPatricia L. Hibberd1,2and Lisa Davidson1Department of Geographic Medicine and Infectious Diseases, Tufts New England Medical Center, and2Tufts University School of Medicine,Boston, Massachusetts1Probiotics have been in widespread use since ancient times and are increasingly being consumed to maintainhealth and to prevent and treat a wide range of conditions. In the United States, probiotics are considered tobe foods or biologics, depending on their intended use. This article addresses the similarities and differencesbetween approaches to conducting clinical trials of probiotics as foods (which leads to health claims) or asbiologics (which leads to therapeutic claims). Most probiotics are manufactured as foods, which makes itchallenging for academic investigators in the United States to meet the requirements of an InvestigationalNew Drug application that enables them to study the therapeutic effects of these novel agents. Although it isimportant to ensure the safety and quality of probiotic products, there also may be value in adapting the USFood and Drug Administration’sGuidance for Industry for Botanical Productsto probiotic products, in partto allow the research agenda to move forward with products for which there are no safety concerns.Shortly after birth, we become colonized by bacteriaand other microbes. The commensal bacteria in ourgastrointestinal tract are crucial to maintaining the in-tegrity and health of the intestinal mucosa [1, 2]. How-ever, these beneficial effects are not limited to the gas-trointestinal tract [3–7]. The ability of commensalbacteria to interact with both the local and the systemicimmune systems holds great promise for the use ofnonpathogenic organisms for prevention and treatmentof a range of diseases [8–12].Probiotics have been in use since ancient times. Inthe early 20th century, Metchnikoff promoted his the-ory that the fermentation of bacteria in dairy productspromotes good health and longevity [13]. Today, pro-biotics are used to prevent and treat a wide variety ofconditions. The evidence is strongest in support of theiruse for gastrointestinal disorders, including diarrhea,pouchitis, inflammatory bowel disease, traveler’s diar-rhea, antibiotic-associated diarrhea, andClostridiumdifficileinfection [14–17]. Other uses have been dis-cussed in other articles of this supplement.Many consider probiotics to be “complementary” or“alternative” medicine. The use of complementary oralternative medicine is increasing rapidly in the UnitedStates. In a 2002 survey, the National Center for Com-plementary and Alternative Medicine, National Insti-tutes of Health, found that 36% of all adults used someform of complementary or alternative medicine in theprevious year [18], and US $36–$47 billion is spentyearly. Natural products (which include probiotics) ac-count for 19% of the complementary or alternativemedicines used annually. US sales of probiotics are es-timated at $764 million (in 2005 US dollars) and areexpected to rise to $1.1 billion by 2010 [19]. In recentyears, the number of published articles on probioticshas increased exponentially (figure 1), but, despite sci-entific interest in and the widespread and growing useof probiotics, few articles are about randomized clinicaltrials. However, the number of National Institutes ofHealth grants for probiotic research (figure 2) and thenumber of ongoing clinical trials of probiotics (figureProbiotic Trial Design and US Regulations•CID 2008:46 (Suppl 2)•S137Downloaded fromby guest on December 16, 2014The contents of this article are solely the responsibility of the authors and donot necessarily represent the official views of the National Center forComplementary and Alternative Medicine, National Institutes of Health.Reprints or correspondence: Dr. Patricia L. Hibberd, Tufts University School ofMedicine, Jaharis 264, 130 Harrison Ave., Boston, MA 02111 (patricia.hibberd@tufts.edu).Clinical Infectious Diseases 2008; 46:S137–402008 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2008/4603S2-0020$15.00DOI: 10.1086/523321Figure 1.Research and randomized trials of probiotics published in the Medline database, 1996–2006Downloaded fromby guest on December 16, 20143) have also increased exponentially, from 1 registered trial inthe United States in 2000 to 20 trials in 2006.Widely available in pharmacies, supermarkets, and healthfood stores, most probiotics that are being studied are sold asfoods or dietary supplements. Are the articles tested in thesestudies foods or drugs? This is a critical question. Most clinicalstudies designed and implemented in the United States evaluateprobiotics to prevent, treat, mitigate, or cure various condi-tions—meeting the conditions for filing an Investigational NewDrug (IND) application with the US Food and Drug Admin-istration (FDA). However, few United States–based trials havebeen conducted under an IND application.Because patients also have access to these products, the safetyand efficacy of probioticsas they are being used by patients(i.e.,as manufactured in accordance with food standards), ratherthan the safety and efficacy of probiotics specifically manufac-tured as drugs, should be evaluated. Alternatively, few wouldargue against a regulatory review that ensures the quality ofboth a product and the clinical trials that are conducted [22].Although the scientific community may view the US regulatorysystem as confusing and as obstructing of scientific advance-ment, these regulatory challenges are an opportunity to im-prove the rationale for, approach to, and quality of clinicaltrials of probiotics that involve patient populations, by askingthe following questions.1. Do we need to understand the precise biological basisof the immunomodulatory effects of probiotics and the effectsof these agents on the gastrointestinal microbiota in animalmodels before human studies are conducted?2. Are preclinical toxicity studies of probiotics that are inwidespread use and that are “generally regarded as safe” nec-essary or useful before development further proceedes withclinical studies?3. How necessary is it to study the effects of probiotics inanimal models of disease before clinical trials are conductedfor specific conditions?4. Is more information on the safety and effects of pro-biotics in healthy people needed, and, if so, how should studiesto obtain this information be designed?5. How should probiotic trials be conducted with “at-risk”populations (e.g., pregnant women, neonates, children, andimmunosuppressed and critically ill patients)?6. Does the dose of probiotics matter, and should it bestudied?7. Is it necessary to use live probiotic organisms, or canbenefit be achieved with dead organisms?8. Should individual probiotic strains be studied separately,or can safety and efficacy profiles be predicted for similarorganisms?9. What are the fundamental requirements to ensure theconsistency, quality, and safety of probiotic products used inclinical trials? In general use?10. For probiotic trials, why are well-recognized standardsfor conducting clinical trials [23] not being followed? Do thestandards differ depending on whether the probiotic is studiedas a dietary supplement or as a biologic?Randomized clinical trials to evaluate the effects of inter-ventions (e.g., through diet, behavior, drugs, biologics, and de-vices) are believed to contribute to evidence-based medicineonly when they meet standards (e.g., as described in the CON-SORT statement) for methodological rigor and high-qualityconduct. The main difference between studies of foods or di-etary supplements and studies of drugs and biologics are thespecific questions addressed and the nature of the product (e.g.,the manufacturing practices required for foods, dietary sup-plements, or drugs). Most manufacturers of probiotic foodsS138•CID 2008:46 (Suppl 2)•Hibberd and DavidsonFigure 2.Basic research grants and clinical research grants from the National Institutes of Health (NIH) for investigations of probiotics. Data arefrom CRISP [20].Downloaded fromby guest on December 16, 2014and supplements are unwilling to meet or are disinterested inmeeting the requirements for good manufacturing practices fordrugs or biologics. These standards are necessary to supportthe IND application for their product to be tested for a “diseaseend point.” As a result, academic clinicians are unable to in-vestigate these products, even though their patients can con-tinue to consume these foods without evidence of safety orefficacy.In 2004, the FDA published a guidance document [24] aboutbotanical products to assist the industry and researchers inunderstanding the US regulatory process and requirements forsuch products. In this document, the FDA defines botanicalproducts as finished, labeled products that contain vegetablematter, which may include plant materials, algae, macroscopicfungi, or combinations of these. Similar to probiotics, mostbotanicals (e.g., ginkgo) have been in widespread use in theUnited States for many years and are often marketed as dietarysupplements. Key features of this 2004 botanical-policy guid-ance document include statements that (1) botanicals that havea documented history of safe prior use in humans, either asforeign drugs, foods, or supplements, are allowed to enter initialclinical trials under an IND application and to proceed withoutprior safety studies in animals; (2) pilot studies are allowed toproceed in the absence of the product meeting the marketingrequirements for chemistry manufacturing and controls for adrug; and (3) the initial clinical trial of a botanical productthat is already widely available to the public may not requirethe typical phase 1 study design used for agents that have neverbeen used in humans. The guidance document describes whatis necessary to meet the requirements for quality control andassurance at different points in the process of product devel-opment. This document for botanicals may provide a valuableFigure 3.Clinical trials investigating probiotics in the United States and elsewhere, 2000–2006. Data are from ClinicalTrials.gov [21].Probiotic Trial Design and US Regulations•CID 2008:46 (Suppl 2)•S139starting point for the FDA to develop a similar guidance doc-ument for probiotics that have been in widespread use for manyyears. As it does with botanicals, the FDA should consider theproduct-specific “track record” of safety for a probiotic sub-mitted under an IND application.The scientific community is at an important crossroads—namely, the determination of whether probiotics are safe andeffective in the treatment of many conditions for which theyare already in widespread use. The growing public interest inprobiotics for disease management necessitates a review of themost basic issues: dosing, safety, and mechanisms of action ofthese agents. Since it is unclear whether data from one strainmay be extrapolated to another, each strain may require sep-arate assessment. This holds true for multistrain combinationsas well. With the promise of genetically engineered microor-ganisms for production of “designer” probiotics, it is even morecritical that the current regulatory impasse be resolved to allowclinical investigations to guide basic, translational, and clinicalresearch in this novel therapeutic area.AcknowledgmentsFinancial support.National Institutes of Health (R13AT003805,K24AT003683, R21AT002133, and R21AT002388).Supplement sponsorship.This article was published as part of a sup-plement entitled “Developing Probiotics as Foods and Drugs: Scientific andRegulatory Challenges,” sponsored by the Drug Information Association,the National Institutes of Health National Center for Complementary andAlternative Medicine (1R13AT003805-01 to Patricia L. Hibberd), the Cal-ifornia Dairy Research Foundation, Chr. Hansen, the Dannon Company,General Mills, Institut Rosell, and Yakult International.Potential conflicts of interest.P.L.H. and L.D.: no conflicts.References1. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, MedzhitovR. Recognition of commensal microflora by toll-like receptors is re-quired for intestinal homeostasis. Cell2004;118:229–41.2. Madsen K, Cornish A, Soper P, et al. Probiotic bacteria enhance murineand human intestinal epithelial barrier function. Gastroenterology2001;121:580–91.3. Nase L, Hatakka K, Savilahti E, et al. Effect of long-term consumptionof a probiotic bacterium,Lactobacillus rhamnosusGG, in milk on dentalcaries and caries risk in children. Caries Res2001;35:412–20.4. Gluck U, Gebbers JO. Ingested probiotics reduce nasal colonizationwith pathogenic bacteria (Staphylococcusaureus, Streptococcus pneu-moniae,andb-hemolyticstreptococci). Am J Clin Nutr2003;77:517–20.5. Hilton E, Rindos P, Isenberg HD.LactobacillusGG vaginal suppositoriesand vaginitis. 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