Mary Ellen Sanders, Ph.D. Consultant, Dairy and Food Culture Technologies Executive Director, International Scientific Association for Probiotics and Prebiotics.

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

Executive Director, International Scientific Association for Probiotics and Prebiotics

[email protected]

Substantiating a health effect for probiotics:

Scientific Perspectives

February 4, 2011

University of Maryland, School of Law

Claims on probiotic productsProduct Food type ClaimsAttune Nutrition

barClinically proven to support digestive health and promote a strong immune system

BioGaia Probiotic Oil-based drops

Reduce colic, improve digestive health and function and boost immunity

DanActive Cultured milk

Helps strengthen the body's natural defenses

Nestlé Good Start Protect Plus

Powdered infant formula

Beneficial cultures like those found in breast milk to help support a baby's healthy immune system

Verb Good Belly Fruit drink Clinically tested to support digestive and immune health

Yakult Cultured milk

Helps balance the digestive system and support immune function

Culturelle Capsule Restores the natural balance of good bacteria in your digestive tract

RepHresh Pro-B Capsule Balances yeast and bacteria to maintain feminine health

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 studiesPublished in peer-reviewed journalsNo flaws (blinding, statistics, etc)Appropriately worded claim language

That accurately reflects the results That meets requirements for product category

Details outlined in FDA guidance documenthttp://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/

DietarySupplements/ucm073200.htm

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

Scientific challenges for probiotic researchers

Regulatory constraints on conducting research

Regulatory framework for product claims

Will an IND be needed?What research pathway

makes both scientific and regulatory sense?

“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

Scientific challenges to establishing causal link between a probiotic and health benefitLack 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

Biomarkers for common “probiotic” endpoints

Endpoint Validated biomarker

Reduced incidence, duration, severity of common infectious diseases

None

Reduced symptoms for IBS, allergy, AAD

None

Improved immune function None

Digestive function Normalized intestinal transit

Improved intestinal microbiotaNormalizing intestinal microbiotaBalancing intestinal microbiota

fecal Bifidobacterium (rejected by EFSA)Decreasing potentially pathogenic intestinal microorganisms

Most probiotic targets do not have validated biomarkersNecessitates full clinical evaluation with meaningful health endpoints

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

Lack of inert placeboBenefit of the product may exceed the magnitude of

the benefit identified in the placebo-controlled studies

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Net effect observed in placebo-controlled study

Effect due to active control

Placebo effect

You can have a blinded study or an inert placebo, but not both

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Scientific challenges to establishing causal link between a probiotic and health benefitLack 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 impossibleMagnitude of effect from a food may be small

Difficult to detect above “noise” of study But…effect must be considered meaningful

Scientific challenges to establishing causal link between a probiotic and health benefitLack 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 impossibleMagnitude of effect from a food may be smallThe 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?

Scientific challenges to establishing causal link between a probiotic and health benefitLack 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 impossibleMagnitude of effect from a food may be smallThe problem of mixed results: not all studies demonstrate

the effect in primary outcome measureNumerous confounders in nutritional studies

Background diet, placebo effect, host microbiota

Human subjects for food/supplement studiesCurrently 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

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

Health DiseaseSymptomsIllness

SyndromesSuboptimal condition

DrugFood

Foods for dietary

management of health conditions Foods that can improve

therapeutic effectiveness

Foods that can reduce the risk of developing an

acute condition

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

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 drugManaging side effects of a drug (eg,

antibiotic)

Foods vs. DrugsDrugs

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

Recommendations from NYAS meeting, June 2010 – online as soon as next week at the Annals of the NYAS

More guidance to industryExpansion of acceptable targets

appropriate for foods/supplements