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
Claims on probiotic products
Product
Attune
Food type Claims
Nutrition Clinically proven to support digestive
bar
health and promote a strong immune
system
BioGaia Probiotic Oil-based Reduce colic, improve digestive health
drops
and function and boost immunity
DanActive
Cultured Helps strengthen the body's natural
milk
defenses
Nestlé Good
Powdered Beneficial cultures like those found in
Start Protect Plus infant
breast milk to help support a baby's
formula
healthy immune system
Verb Good Belly Fruit drink Clinically tested to support digestive and
immune health
Yakult
Cultured Helps balance the digestive system and
milk
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 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/DietarySuppleme
nts/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
Will an IND be needed?
Regulatory framework for
product claims
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 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
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 microbiota
Normalizing intestinal microbiota
Balancing intestinal microbiota
 fecal Bifidobacterium (rejected by
EFSA)
Decreasing potentially pathogenic
intestinal microorganisms
Most probiotic targets do not have validated biomarkers
Necessitates full clinical evaluation with meaningful health endpoints
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
Arbitrary digestive endpoint units
35
Net effect observed in
placebo-controlled study
30
25
Effect due to active control
20
baseline
15
post treatment
Placebo effect
10
5
0
No intervention
yogurt control
probiotic yogurt
You can have a blinded study or an inert placebo, but not both
Total benefit of product consumption
Lack of inert placebo
Benefit of the product may exceed the magnitude of
the benefit identified in the placebo-controlled studies
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
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?
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
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
Does the current regulatory framework
inhibit research on probiotics for
foods/supplements?
Boxes vs. continua
Health
Food
Symptoms
Illness
Foods for
dietary
management of
health conditions
Syndromes
Suboptimal
condition
Disease
Foods that can reduce the
risk of developing an
acute condition
Foods that can improve
therapeutic effectiveness
Drug
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
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 effect
2. Nor on publicly-funded studies conducted on foods in the US
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)
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
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