Assessing the Suitability of Application of Traditional Clinical Trial to Food

Transcription

1 Assessing the Suitability of Application of Traditional Clinical Trial to Food Theo Ockhuizen 1

2 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. 2

3 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. 3

4 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 No system specific (artichoke). health claims. A variety Works on of food the vascular items and system food and supplements. helping to maintain healthy blood circulation, which in 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). 4

5 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). 5

6 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. 6

7 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. 7

8 Hierarchy of research methodology* *Systematic Reviews: CRD s guidance for undertaking reviews in healthcare, ISBN: Systematic review/meta-analysis Interventions: Randomized controlled trial - cross-over trials - cluster randomized trials Confidence in results Quasi-experimental studies - non-randomized controlled trials - before and after studies - interrupted time series Observational: Cohort study Case control studies Cross sectional studies Case series 8

9 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. 9

10 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). 10

11 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. 11

12 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 12

13 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,

14 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,

15 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,

16 Pharma-/nutritional approach Let food be thy medicine, and thy medicine thy food (Hippocrates, 5th Century BC) Indicators for health status. Pharma- and disease biomarkers are not suitable to define health. New nutritional evidence. 16

17 Pharma and nutrition green and van der ouderaa, nature pharmacogenomics (2003) 17

18 Pharma- and disease biomarkers are not suitable to define health Quantitation of health Quantification of disease Predisposition Elasticity in homeostasis Multiple biomarkers Time course Morphology System physiology Inter-individual variation Intra-individual variations over time Disposition Change in homeostasis Single biomarker Time point Histopathology Organ pathology Clear sub phenotypes Defined disease progress Van Ommen et al,

19 The use of biomarkers Markers of exposure to food component Markers of target function/ biol. response Markers of intermediate end point Claims of enhanced functions: Improves natural defence Claim of reduced risk of disease: reduces the risk of cardiovascular disease 19

20 Get healthy people more healthy Gradual transition: apparently healthy to disease Late biomarkers nutrition pharma Biomarkers for disease risk disease healthy Time 20

21 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.. 21

22 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. 22

23 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. 23

24 Way forward No change in EFSA s approach Special category: new criteria Golden 10 Medical legislation 24

25 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). 25

26 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. 26

27 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. 27

28 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. 28

29 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 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. 29

30 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. 30

31 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. 31

32 Thank you for your attention 32