Mary Ellen Sanders, Ph.D. Consultant, Dairy and Food Culture Technologies

1. Substantiating a health effect for probiotics: Scientific Perspectives February 4, 2011 University of Maryland, School of Law Mary Ellen Sanders, Ph.D. Consultant, Dairy and Food Culture Technologies Executive Director, International Scientific Association for Probiotics and Prebiotics mes@mesanders.com

2. Claims on probiotic products

3. Evidence for substantiation of food/supplement claims in the U.S.: the “Holy Grail” • RDBPC trial (preferably more than one by different research groups) • in population that reflects the target population (general population for supplements) • using product format identical to that to be sold (strains, other functional ingredients, delivery format) • with endpoint appropriate for product category (structure/function of the human body or reduction of risk disease) • Consistent results among different studies • Published in peer-reviewed journals • No flaws (blinding, statistics, etc) • Appropriately worded claim language • That accurately reflects the results • That meets requirements for product category Details outlined in FDA guidance document http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/DietarySupplements/ucm073200.htm

4. FDA/FTC assessments of evidence allows petitioner to provide “scientific rationale” for approach to substantiation Provides some flexibility IF a legitimate scientific rationale is provided

6. Scientific challenges for probiotic researchers Regulatory constraints on conducting research Regulatory framework for product claims What research pathway makes both scientific and regulatory sense? Will an IND be needed? “It may not always make scientific sense but that is what is in the regulation and that is what we must follow,” professor Albert Flynn, chairman of the NDA panel of European Food Safety Authority said on December 2nd 2010

7. Scientific challenges to establishing causal link between a probiotic and health benefit • Lack of validated biomarkers for “probiotic” endpoints. • Research targets often are on endpoints that are not measurable with validated biomarkers and have no recognized risk factors that are intermediate measures of health responses. • Instead target clinical endpoints

8. Biomarkers for common “probiotic” endpoints Most probiotic targets do not have validated biomarkers Necessitates full clinical evaluation with meaningful health endpoints

9. Scientific challenges to establishing causal link between a probiotic and health benefit • Lack of validated biomarkers for “probiotic” endpoints. • Choice of placebo: inert placebo may be impossible

10. Lack of inertplaceboBenefit of the product may exceed the magnitude of the benefit identified in the placebo-controlled studies Net effect observed in placebo-controlled study Effect due to active control Arbitrary digestive endpoint units Total benefit of product consumption Placebo effect You can have a blinded study or an inert placebo, but not both

11. Scientific challenges to establishing causal link between a probiotic and health benefit • Lack of validated biomarkers for “probiotic” endpoints. • Research targets often are on endpoints that are not measurable with validated biomarkers and have no recognized risk factors that are intermediate measures of health responses. • Choice of placebo: inert placebo may be impossible • Magnitude of effect from a food may be small • Difficult to detect above “noise” of study • But…effect must be considered meaningful

12. Scientific challenges to establishing causal link between a probiotic and health benefit • Lack of validated biomarkers for “probiotic” endpoints. • Research targets often are on endpoints that are not measurable with validated biomarkers and have no recognized risk factors that are intermediate measures of health responses. • Choice of placebo: inert placebo may be impossible • Magnitude of effect from a food may be small • The problem of mixed results: not all studies demonstrate the effect in primary outcome measure • High placebo effect • Underpowered study In reviewing “totality of evidence”, does a “negative” study negate legitimacy of a study which documents the effect?

13. Scientific challenges to establishing causal link between a probiotic and health benefit • Lack of validated biomarkers for “probiotic” endpoints. • Research targets often are on endpoints that are not measurable with validated biomarkers and have no recognized risk factors that are intermediate measures of health responses. • Choice of placebo: inert placebo may be impossible • Magnitude of effect from a food may be small • The problem of mixed results: not all studies demonstrate the effect in primary outcome measure • Numerous confounders in nutritional studies • Background diet, placebo effect, host microbiota

14. Human subjects for food/supplement studies • Currently healthy or at-risk individuals • Effects in healthy people can require very large number of subjects • Identifying responders prior to recruitment can decrease number of subjects needed, but often can’t distinguish responders from non-responders? • Representative of the target population • If have broad inclusion criteria, study will have more noise • If narrow inclusion criteria, study may not represent the target population • Homogeneous study population reduces “noise”, but may be criticized for not reflecting general population

15. Does the current regulatory framework inhibit research on probiotics for foods/supplements?

16. Boxes vs. continua Syndromes Symptoms Health Disease Suboptimal condition Illness Foods for dietary management of health conditions Foods that can reduce the risk of developing an acute condition Food Drug Foods that can improve therapeutic effectiveness

17. Regulatory “interpretations” that may inhibit probiotic research • Reluctance of regulators to accept concept of healthy gut microbiota • Requirements for INDs, even if IRB’s deem the study is safe: researchers are wary of FDA reprisal • Very high standard for evidence required for probiotic foods/supplements may discourage industry investment in research: no ROI and may drive product costs to unrealistic levels • Substantial equivalency: • More complicated with foods: foods deliver a “package” of nutrition, functional ingredients, sensory properties and convenience • Product format changes are the norm • Unattainable to test numerous product formats in human studies • Products are consumed in the context of a varied diet • Need reasonable approach to concluding “substantial equivalency: • Research to support information HCPs would like to have for safe, dietary interventions for their patients • Is the food safe for my patients? • How can it help my patients prevent or cope with getting sick? • Current S/F claim language is not precise enough to communicate product benefits

18. Currently… When your doctor tells you to eat a yogurt if you have trouble tolerating an antibiotic or if you are susceptible to vaginal infections, he cannot base this recommendation on:1. Communications by companies that their yogurt has been tested and shown to have this effect2. Nor on publicly-funded studies conducted on foods in the US

19. Probiotic foods: What is the harm in their use for dietary management of… • Reducing risk of acute diseases (colds, flu, GI infections) • Managing symptoms in persons who are not fully healthy (IBS) • Improving therapeutic efficacy of a drug • Managing side effects of a drug (eg, antibiotic)

20. Foods vs. Drugs • Drugs • The hurdle to market is big • Drugs are expensive • Side effects can be serious • Magnitude of physiological effect can be large • Food/supplement • Easier path to market • Product cost is lower • A smaller magnitude of physiological effect is acceptable • Many probiotics have been used safely in a variety of ages, health conditions and doses

21. Recommendations from NYAS meeting, June 2010 – online as soon as next week at the Annals of the NYAS • More guidance to industry • Expansion of acceptable targets appropriate for foods/supplements