European Legislation applied for Probiotics (food ...€¦ · European Legislation applied for...

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European Legislation applied for Probiotics (food, supplements and medicines)

Björn Lindman, BioGaia AB

Probiotic microorganism

Within the EU:

There are no special regulations or laws related to the regulation of products containing probiotics!


Food products

Regulation (EC) No 178/2002:

Article 2Definition of ‘food’For the purposes of this Regulation, ‘food’ (or ‘foodstuff’) means any substance or product, whether processed, partially processed or unprocessed, intended to be, or reasonably expected to be ingested by humans. ‘Food’ includes drink, chewing gum and any substance including water, intentionally incorporated into the food during its manufacture, preparation or treatment.

Medicinal products

Directive 2001/83 of the European Parliament and of the Council:Medicinal product:(a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or(b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis

Substance:Any matter irrespective of origin which may be:…— micro-organisms,…


Food products Medicinal products

FoodstuffFood supplementSpecial food:

Food for special medical purposes (FSMP)Infant formula

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A probiotic microorganism is regarded and treated as any other (food) constituent.

A probiotic microorganism is regarded and treated as any other Active Pharmaceutical Ingredient (API).



Regulation (EU) 2015/2283 on novel food:

If not used ”to a significant degree” before “15 May 1997” a novel food must obtain the EU Commission’s authorisation and be put on the “Union list” as such.

A novel microorganism will after approval be put on the QPS list (Qualified Presumption of safety).

Safety

Application assessed by European Food Safety Authority (EFSA).

Decision made the EU Commission

Regulation (EU) 726/2004 on authorisation of medicinal products:

”medicinal product…” “may be granted a market authorisation by the Community in accordance with the provisions...”

Efficacy and safety

Application assessed by European Medicines Agency (EMA) (or by national MPA).

Decision made by EMA (or by national MPA)

New New



Efficacy:Treating or preventing disease in human beings

Efficacy:Regulation (EC) No 1924/2006 on health claims:1) ‘claim’ means any message or representation, which states, suggests or implies that a food has particular characteristics;2) ‘nutrient’ means protein, carbohydrate, fat, fibre, sodium, vitamins and minerals3) ‘other substance’ means a substance other than a nutrient that has a nutritional or physiological effect;4) ‘nutrition claim’ means…5) ‘health claim’ means any claim that states, suggests or implies that a relationship exists between a food category, a food or one of its constituents and health;6) ‘reduction of disease risk claim’ means any health claim that states, suggests or implies that the consumption of a food category, a food or one of its constituents significantly reduces a risk factor in the development of a human disease;




Efficacy:Regulation (EC) No 1924/2006 on health claims:

Article 13Health claims other than those referring to the reduction of disease risk and to children's development and health.

13.1 Health claims describing or referring to:the role of a nutrient or other substance in growth, development and the functions of the body;

(i) based on generally accepted scientific evidence;





Article 13Health claims other than those referring to the reduction of disease risk and to children's development and health.

13.5 Any additions of claims to the list referred to in paragraph 3 based on newly developed scientific evidence and/or which include a request for the protection of proprietary data shall be adopted following the procedure laid down…





Article 14Reduction of disease risk claims and claims referring to children's development and health.

14.1(a) Reduction of disease risk claims

14.1(b) Claims referring to children's development and health.



Efficacy substantiation:

The substantiation requirements for the efficacy of a product with a live microorganism as API are not different from those with a molecule as API:

Enter into a framework of regulations related to the regulation of:Registration of your anticipated investigational new medicineDesign of clinical trials encompassing large cohorts of subjects (1000:s of patients)Etc.

Way of working (GMP)

Efficacy substantiation:Regulation (EC) No 1924/2006 on health claims:

“A claim should be scientifically substantiated by taking into account the totality of the available scientific data, and by weighing the evidence.”

”Health claims should only be authorised for use in the Community after a scientific assessment of the highest possible standard”


Food products

Efficacy substantiation requirements:

How should those words in Regulation No 1924/2006 be understood?What do I actually need to do to prove my claim?

History tells us:

Requirements not fully understood by industryWording not clear enough


Food products


L. helveticusL. johnsoniiL. paracaseiL. plantarumL. reuteriL. rhamnosusP. freundenreichiiS. cereviseae

Species subjected to health claim application so far:

B. animalisB. bifidumB. longumL. acidophilusL. caseiL. delbrueckiiL. fermentumL. gasseriL. helveticus


Food products


Guidance on the scientific requirements for health claims related to gut and immune function; EFSA NDA panel, 2011:

“Whether the studies have been carried out in a study group representative of the population group for which the claim is intended. Can the results obtained in the studied population be extrapolated to the target population? For studies in groups (e.g. subjects with a disease) other than the target group for a claim (e.g. the general population), the NDA Panel considers on a case-by-case basis the extent to which it is established that extrapolation from the study group to the target group is biologically justifiable.”


Food products


On the scientific requirements for health claims; EFSA NDA panel seminar, 2012:

“Two well designed clinical studies involving 30-50 objects and with a statistically sound outcome will usually suffice”


Food products


Up until now (2016)

199 probiotic claim applications have been assessed by EFSA (the panel on Nutrition, Dietetic products and Allergies (NDA))

Not a single claim has been approved!


Food products


Initial optimism:

EFSA was drowned in health claim applications (about 4500)

Took EFSA several years before the first batch of statements (Scientific Opinions) were published


Food products


Why rejected?

Strain not sufficiently characterisedClaim not beneficialStudy on wrong strain

Study did not address/measure the relationship between strain and claimed effect

Methodological (computational/practical) shortcomings in clinical studyQuestionnaire not validated

190 applications

2008 - 2012

(139)

On basic grounds

On medium-level grounds

On high-levelgrounds

(26)

(25)


Food products


Why rejected?

Strain not sufficiently characterisedClaim not beneficialStudy on wrong strain

Study did not address/measure the relationship between strain and claimed effect

Methodological (computational/practical) shortcomings in clinical studyQuestionnaire not validated

9 applications

2013 - 2016

On basic grounds

On medium-level grounds

On high-levelgrounds

(9)


Food products


Regulation (EC) No 1924/2006 on health claims:

“A claim should be scientifically substantiated by taking into account the totality of the available scientific data, and by weighing the evidence.”

”Health claims should only be authorised for use in the Community after a scientific assessment of the highest possible standard”

Guidance on the scientific requirements for health claims related to immune system, the gastrointestinal tract and defence against pathogenic microorganisms; EFSA NDA panel, Jan. 2016:

“According to the Regulation, health claims should only be authorised for use in the Community after a scientific assessment of the highest possible standard has been carried out by EFSA”


Food products


Scientific OpinionLactobacillus plantarum 299v and an increase of non-haem iron absorption: evaluation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006; EFSA NDA panel, June 2016:

”Sequential, non-randomised order of administration of the control and test foodsmay have introduced a systematic bias to the results of these studies.”

”On the basis of the data presented, the Panel concludes that the scientific evidence is insufficient to establish a cause and effect relationship between the consumption of Lp299v and an increase of non-haem iron absorption.”


Food products


Lesson learned:

Clinical trials design must not leave room for any doubt. Randomized, double blind and placebo controlled trial should be preferred.

Validated questionnaires

Adequate statistics; no methodological errors/gaps or computational flaws

Results of clinical trials is the only key to success.

Thankyou

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