Transcript EFSA guidance document 29 Sept 2010

Assessing the Suitability of Application of
Traditional Clinical Trial to Food
Theo Ockhuizen
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Main topics
as requested by the organizing committee
Assessing the Suitability of Application of Traditional Clinical Trials to Food Supplements
 Analysing main business issues with
presenting the authorities with
“suitable” clinical data.
 Exploring the effect of application of
clinical trials to new products on
healthy business competition.
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Our future diet

Food is essential part of growth and
development.

Focus on optimal metabolic health.

Major diseases can be prevented,
postponed or cured by diet.

We live more than 100 years & grow
taller & taller.

Food adds years to life and life to
years.
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Botanicals: examples of claimed benefits

Helping to maintain a healthy cholesterol level (garlic).

Useful aid in maintaining normal weight (green tea).
Conclusions:
Helping women to relief menopausal discomfort (soy).
 Botanical health claims cover a variety of generic symptoms
 Beneficial effects on the functioning of the liver and maintaining a healthy digestive
(artichoke).
Nosystem
specific
health claims.
A variety
Works on
the vascular
system
helping to maintain healthy blood circulation, which in
of food
items and
food and
supplements.
turn impacts mental and cognitive processes (ginkgo).
 Different working mechanisms.
 Beneficial effect on cognitive and mental health, helps to maintain positive mood and
cognitive function (lemon balm).

Prevent infection of the lower urinary tract (cranberry).
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EFSA & EU Regulation 1924/2006
EFSA guidance: 3 main questions to be addressed
The extent to which:
1. the food/constituent is defined and characterised (in relation to the claimed effect).
2. the claimed effect is defined and is a beneficial physiological effect (‘beneficial to human
health’).
3. a cause and effect relationship is established between the consumption of the
food/constituent and the claimed effect (for the target group under the proposed conditions
of use).
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EFSA guidance
Target population
Cover range of target population:
 Age
 Sex
 BMI
 ‘Healthy’ or ‘healthy at risk’
 Normal diet – but assess!
 Inclusion/exclusion criteria
Population group:
 Study group representative of general population?
– Health claims are intended for the general (healthy) population or specific subgroups:
elderly, athletes, pregnant women.
– Case-by-case with disease studies/extrapolation/ biological plausibility.
 When a health claim relates to a function/effect that may be associated with a disease,
subjects with the disease are not the claim target (e.g. joint health, etc).
 Appropriate outcome measures?
– What is generally accepted in relevant research fields
– NDA consults experts from various appropriate disciplines.
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EFSA guidance
Human studies

In weighing the evidence EFSA (NDA panel) considers all scientific pertinent data
hierarchy of evidence
Clinical
Human
Confidence in results
Epidemiology
Animal

Human studies are central for EFSA for the substantiation of a health claim
- human intervention studies
- human observational studies

Studies in animals or in vitro may provide supportive evidence.

Not different from other standards like CODEX, FDA.
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Hierarchy of research methodology*
*Systematic
Reviews: CRD’s guidance for undertaking reviews in healthcare, ISBN: 1900640473
Systematic review/meta-analysis
Interventions:
Quasi-experimental studies
- non-randomized controlled trials
- before and after studies
- interrupted time series
Confidence in
results
Observational:
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Randomized controlled trial
- cross-over trials
- cluster randomized trials
Cohort study
Case control studies
Cross sectional studies
Case series
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EFSA
Final verdict
Three levels of final conclusion after scientific evaluation:
 Cause and effect established:
 Sufficient conclusive evidence
 General accepted science.

Cause and effect relationship not established:
 (very) limited scientific evidence.

Insufficient evidence to establish cause and effect
 Some evidence but not conclusive
 Emerging science
 Conflicting results.
Current status
225 approved nutrition and health claims.
44 botanical claims rejected.
Botanicals on hold.
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Botanicals: reactions
EHPM (European Federation of Associations of Health Product Manufacturers )
Early rejections due to uncertainty (Nov. & Dec. 2011):
 Do not automatically consider claims that have received negative opinions as rejected.
 Unfavourable EFSA opinions are not due for reasons that a cause and effect was not
established, but because:
the information provided didn’t meet the expectations,
the opinions were not within the scope of the NHCR, and
The use of inappropriate assessment criteria.
EFSA’s approach for the assessment of Article 13.1 claims (May 17, 2012):
 Is not in line with the proportionality foreseen by the regulation.
 The pharmaceutical-type criteria are not appropriate for nutrition science.
 Requires a re-think of the legislation (specific health claims for botanical food
supplements).
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Botanicals reactions
BEUC (Bureau Européen des Unions de Consommateurs)
 BEUC sees no justification for a different treatment of botanicals and strongly warns
against moving away from the rigorous scientific assessment.
 “ Tradition of use” does not equate efficacy as shown by EFSA’s negative verdict on a first
series of botanical claims which, although they are wide-spread across the EU, turned out
not to be backed by science.
 It is high time that these claims are taken of from the market: this does not mean that
the botanicals bearing these claims will disappear but simply that they will no longer be
able to carry misleading, unsubstantiated health messages.
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Implications
1. Dietary supplements are targeted at the general population (i.e., healthy people, not
patients). In order to carry a health claim, a randomized, double-blind, placebocontrolled clinical trial with a sufficiently high number of subjects must be conducted
proving efficacy.
2. EFSA requires that the study population be equivalent to the target population. In
effect, the trial must prove that healthy subjects get more healthy?
3. Clinical research organizations are using approved biomarkers as study end points,
but the fact remains it is not as simple to prove the efficacy of an ingredient on
healthy people as it is on patients.
4. Inappropriate assessment criteria.
5. Re-think legislation; include “traditional use”.
6. Pharma approach does not suit nutritional science
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Proper study design:
double-blind, placebo-controlled clinical trial*
Food
 Characterize food/ingredient .
 Dose used should be same as consumer recommendation; ideally do dose response.
 Appropriate placebo.
Dietary assessment
 It is not justified that dietary assessment should be a mandate for accepting a DBPC
trial, but it is a good practice to do it.
 Recording diet may change the eating habits during the intervention.
Design study to support claim: causal relationship
 Define claim.
 Commercial dose.
 Realistic duration.
 Subjects must cover range of consumers (age, sex, BMI etc).
 Normal diet.
 Inclusion/exclusion criteria well-described.
•The design of probiotic studies to substantiate health claims, Gibson et al, Gut Microbes 2:5, 1-7, 2011
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Proper study design:
double-blind, placebo-controlled clinical trial*
Design of clinical trial: study to maximize chance of detecting an effect
 Large dose, n doses/day.
 Use subjects with greatest sensitivity to effect.
 Cover range of target population: patients, healthy subjects or health at risk, single sex, age, etc.
 Control background diet (and assess diet) and conditions.
 Strict inclusion/exclusion criteria.
 Measure compliance.
Design of clinical trial: statistics
 Consult statistician

RDBPCT

Parallel or cross-over

Length of study – appropriate for end point + relate to real-life use

Cover all the bases - multidisciplinary team.
 Primary end point

Preferably ‘hard’ end point with clinical support

Include biomarker(s) to help mechanisms/causality.
 Power calculation

Size of effect, biological importance.
 Multiple sample times.
 Take & store additional samples for future tests
•The design of probiotic studies to substantiate health claims, Gibson et al, Gut Microbes 2:5, 1-7, 2011
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Proper study design:
double-blind, placebo-controlled clinical trial*
Lessons from NDA opinions
Don’t

Extrapolate data from subjects in pathological conditions to the healthy population.

Establish a link with health must be carefully identified, avoiding the use of
immeasurable/generic features.
Do

Human studies (intention to treat, randomisation, double blinding, control group, crossover) with statistical power is mandatory (centralised protocol design).

Measure the effects by means of biomarkers with a scientific consensus and an analytical
tool.
•The design of probiotic studies to substantiate health claims, Gibson et al, Gut Microbes 2:5, 1-7, 2011
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Pharma-/nutritional approach
‘Let food be thy medicine, and thy medicine thy food’
(Hippocrates, 5th Century BC)



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Indicators for health status.
Pharma- and disease biomarkers are not suitable to define health.
New nutritional evidence.
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Pharma and nutrition
green and van der ouderaa, nature pharmacogenomics (2003)
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Pharma- and disease biomarkers are
not suitable to define health
Quantitation of health
Quantification of disease
 Predisposition

Disposition
 Elasticity in homeostasis

Change in homeostasis
 Multiple biomarkers

Single biomarker
 Time course

Time point
 Morphology

Histopathology
 System physiology

Organ pathology
 Inter-individual variation

Clear sub phenotypes
 Intra-individual variations over time

Defined disease progress
Van Ommen et al, 2008
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The use of biomarkers
Markers of
exposure to
food component
Markers of
target
function/
biol. response
Claims of enhanced functions:
“Improves natural defence”
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Markers of
intermediate
end point
Claim of reduced risk of disease:
“reduces the risk of cardiovascular
disease”
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Get healthy people more healthy
Gradual transition: apparently healthy to disease
Late biomarkers
nutrition
pharma
“disease”
Biomarkers for disease risk
“healthy”
Time
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Processes as indicators for health status
(“surrogate health indicators”)
•
•
•
•
•
•
•
•
Low grade inflammation
(metinflammation)
Metabolism
Oxidative stress
Vascular function
Stress responses
Intestinal permeability
Composition of intestinal flora
…..
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Need for new strategy
Nutritional products* are different from pharmaceutical preparations
 Application (health vs disease; target groups etc).
 Biological activity of active ingredients and time dependence of effects.
 Risk-benefit ratio.
 Regulatory framework.
* As defined by EU legislation
So we need new strategies
 Effects slow and subtle.
 Variations in preparations.
 Mixtures.
 Inter-individual variations.
 Pharma-and disease biomarkers not suitable.
 Target population is healthy.
 Economical considerations.
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New nutritional evidence
Nutrition should target the boundaries between health and disease
 Slightly elevated blood pressure.
 Slightly reduced insulin response.
 Slightly abnormal lipids.
 Mild liver damage.
 Elevated mediators of inflammation
Challenges
Toolbox of accepted methodologies is outdated. Develop new concepts.
Statistics and causality should be clearly separated.
Dietary- and product orientation must be integrated.
From Benefit towards a Risk-Benefit approach.
A participative strategy is demanded. Work closely together with industry.
Learn from other domains where complexity plays a large role.
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Way forward
 No change in EFSA’s approach
 Special category: new criteria
 “Golden 10”
 Medical legislation
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Way forward: no change in approach
Current situation for health claims made on herbal products
 Many plants that are clearly medicinal such as Ginkgo biloba and St. John’s wort, are being sold in
dietary supplements at daily dosages below the pharmacologically effective range and have been for
decades. These old products can continue to use their claims until the health claim situation for
botanicals is resolved.
No change in EFSA’s approach to judge health claims
 If an ingredient is to be used in a dietary supplement, which is part of the food category, EFSA requires
no less than gold standard clinical trials as proof of efficacy in order to carry a product-specific health
claim.
Main business issues
•
If a claim for a botanical supplement can be substantiated it will never be generic but always be
restricted in its application.
•
The required clinical studies will be expensive and thus limiting the options of SME’s.
Financing fundamental studies in biomarkers, intermediate end points and clinical studies will require
collaboration in consortia.
•
Consider collaboration with other industries for developing new strategies, consensus biomarkers,
intermediate end points, etc.
•
EHPM is of the opinion that the assessment of health claims on botanicals with no change in the
approach will not solve any of the problems on the table (Aug. 27, 2012).
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Way forward: no change in approach
Exploring the effect of application of clinical trials to new products on healthy business competition.
 New botanical products “without a history of traditional use” will require a dossier fulfilling the EFSA
guidelines including clinical trials to obtain a health claim under the current NHCR.
 This will be extremely difficult and expensive.
 Thus, if health claims on botanicals will only be allowed according to the principle of “tradition of use”,
it will exclude new products from health claims (or force them to conduct expensive trials) and will
create an unhealthy business competition.
Moreover
 With no changes to the approach towards traditional use, most of the health claims on botanicals will
no longer be authorized, while medicinal claims will continue to be allowed based only on ‘traditional
use’.
 This, again, would create an unfair competitive situation between the pharmaceutical and food
supplement sectors.
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Way forward: special category
Review legislation
Unless EFSA decides to re-think its criteria for approving a health claim, most of the
applied health claims for botanicals will be rejected, and thus, even if and when an
assessment is made, it still won’t be possible for most botanicals to carry health claims.
EFSA’s option 2: to address the assessment of botanical health claims through a review of
the legislation.
EHPM : The only way forward is to rely on traditional use (Aug. 27, 2012).
Tradition of use
To prove efficacy, a Traditional Herbal Medicinal Product (note the “medicinal”) needs
nothing more than a proof of tradition (a continuous use of the product for 30 years on the
market) in order to carry health claims.
The current EFSA approach does not consider traditional information alone as sufficient
evidence for the substantiation of a claim.
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Way forward: “Golden 10”
Golden 10:
 In case of for instance a claim like “supporting the immune system” a way forward for a (new)
supplement product containing botanicals to put “immune” health claims on its label is to add a
vitamin or mineral or other substance that can carry approved health claims and use those.
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Way forward: alternative route
EU medical devices:
 As long as this situation continues, the only way a purely botanical product can carry health
claims is through registration as a medicinal (Traditional Herbal Medicinal) product.

It seems that the requirements for a medicinal product are actually lower than for a food
product.

In fact, the herbal medicinal products route is looking more and more attractive for
manufacturers; they will have to invest in a clinical trial in any case, so they might as well aim for
the higher margins that a drug product can offer.

European Union medicines agencies are reporting increasing numbers of ‘medical device’
applications for food supplement products rejected under strict EU health claim laws.

These include fibre, cranberry, chitosan and other supplements featuring nutrients on the now
enforceable EU nutrition and health claims regulation (NHCR) list of 1500+ non-authorised
health associations.

The European Federation of Associations of Health Product Manufacturers (EHPM) have been
advising members affected by the NHCR to consider applying for medical devices registrations.
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Wrap up (1)
Unsuccessful claim application
• The pharma-based evaluation criteria, used by EFSA in the assessment of health claims,
are prohibitive for botanicals for a successful application. Currently and in the future
probably as well.
• Current claims on botanicals are too broadly defined for an assessment in clinical trials.
Insufficient toolbox
• The toolbox of nutritional research to substantiate health claims according to pharmabased criteria is currently insufficient. New strategies are needed.
• For instance, recent developments in the genomics-field may provide solutions to
define health markers in health people.
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Wrap up (2)
Need for collaboration
• A lot of fundamental research will be needed for consensus in study design, biomarkers
and intermediate endpoints.
• Inter-sectorial collaboration as well as pre-competitive collaboration with other sectors,
for instance probiotics, is essential for funding fundamental research and clinical
studies.
• Special legislation for botanicals, using “30 years of traditional use” is subject of public
debate with conflicting opinions. The outcome of the political debate is yet unclear.
New products
• Introduction of new botanical supplements with a substantiated, EFSA approved health
claim under the current assessment criteria, will be extremely difficult if not impossible.
Moreover, if the principle of “tradition in use” will be applied for these new botanical
supplements, a health claim will be impossible as well.
• A currently popular way out procedure for existing botanicals is the EU Medical Device
Law.
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Thank you for your attention
[email protected]
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