an integrated systems-based model for substantiation of health claims in functional food development
TRANSCRIPT
Trends in Food Science & Technology xx (2014) 1e6
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* Corresponding author.
http://dx.doi.org/10.1016/j.tifs.2014.09.0060924-2244/� 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Younesi, E., & Ayseli, M. T., An inte
development, Trends in Food Science & Technology (2014), http://dx.
An integrated
systems-based model
for substantiation of
health claims in
functional food
development
Erfan Younesia,* and
Mehmet Turan AyselibaFraunhofer Institute for Algorithms and Scientific
Computing SCAI, Schloss Birlinghoven, 53754 Sankt
Augustin, Germany (Tel.: D49 15203401108; e-mail:
[email protected])bGenetris LLC, Kiremithane Mah, 4413 Sok. Akkurt
Apt. K:1 D:2 Akdeniz, Mersin, Turkey (e-mail: tayseli@
genetris.com)
There is a pressing need for new innovative models to boost
functional food production processes. However, it is not clear
how the food industry can technologically transform its tradi-
tional NPD model into a modern, integrated NPD pipeline
that can satisfy regulatory and consumer demands, on one
hand, and enhance the capacity for innovation and competi-
tion, on the other hand.
We provide a new perspective on how systems-based ap-
proaches may practically enable the food industry to support
substantiation of health claims for their innovative functional
products and to reduce the time and cost of risky decisions
associated with clinical trials.
IntroductionFunctional food represents the fast growing category in theUS food market with an annual rate of 8.6e20 percent(Smith & Charter, 2011). Although, in the absence of a
grated s
doi.org/1
controlled vocabulary or standard terminology, there is nouniversal definition for “functional food” and “nutraceuti-cal” and these two terms have been often used interchange-ably, a ‘nutraceutical’ has been defined as “a food or part ofa food that provides medical or health benefits, includingthe prevention and/or treatment of a disease” (Brower,1998). Doyon and Labrecque (2008) performed an exhaus-tive analysis on 26 proposed definitions for ‘functionalfood’ in literature and generated the following workingdefinition: “A functional food is, or appears similar to, aconventional food. It is part of a standard diet and isconsumed on a regular basis, in normal quantities. It hasproven health benefits that reduce the risk of specificchronic diseases or beneficially affect target functionsbeyond its basic nutritional functions.” Based on these def-initions, both functional foods and nutraceuticals aim atstrengthening physiological functions (health promotion)through enhancement of mental and physiological perfor-mance, reduction of the disease risk, and treatment ofhealth problems (Andlauer & Furst, 2002).
Historically, the concept of “food as medicine” was firstsuggested by medieval Persian practitioners such as Avi-cenna and Rhazes who developed scientific guidelines onthe use of natural products for treatment of diseases andhealth problems (Nikaein, Zargaran, & Mehdizadeh,2012). This concept was shadowed by the advent of moderndrug development technology but, for two main reasons,the important role of functional food in health promotionhas again gained increasing attention: first, the current“one size fits all” paradigm with synthesized drugs in phar-maceutical industry has been greatly challenged by incom-patibility of new drug candidates with the complex naturalsystem of the human body, leading to toxicities and side-effects (safety issue); second, increasing attrition rates indrug development pipelines, on one hand, and inability ofcurrent diagnostic and therapeutic strategies to diagnoseand intervene early in progressive cascade of the chronicdiseases such as dementia or cancer, on the other hand (ef-ficacy issues), has encouraged both pharmaceutical andfood industries to focus on the disease prevention and treat-ment using functional, natural compounds (Sharma & Tan,2013).
Currently a convergence between the food and pharma-ceutical industries is witnessed due to a paradigm shift fromtraditional food NPD to functional food NPD so thatboundaries between the two industries are blurring in terms
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of technologies and demand structures (Br€oring, MartinCloutier, & Leker, 2006). However, R&D competencies be-tween the two sectors are different, and in this regard, weagree with the roadmap proposed by Khan, Grigor,Winger, and Win (2013) in their recent review where theyhighlight the need for the food industry to evolve fromtraditional NPD toward an integrative and innovativeNPD portfolio. This roadmap draws on established techno-logical capabilities of the pharmaceutical industry in termsof “knowledge generation activities” to support safety andefficacy of novel bioactive ingredients. In contrast toKhan and colleagues who focused on the organizational re-quirements, we draw the attention to technological develop-ment required for generation of knowledge and extend ontheir roadmap for functional food NPD from a technolog-ical perspective.
Shifting trend in functional food product developmentTackling the complex biology of human chronic diseases,
which has been the focus of the pharma industry for manyyears, poses a new challenge to the food industry if safetyand efficacy of the functional food products are to be shown.The pressure on food manufacturers is increasing to copewith stringent regulatory demands required for substantiationof health claims for functional products. For example, theFood and Drug Administration (FDA) e responsible for pro-tecting public health through the regulation of food safety inthe U.S. e does not recognize functional food as a food cate-gory and accordingly, food and beverage products with healthclaims are considered to be drugs andmustmeet theFDA’s reg-ulatory requirements, including proof of safety and efficacy.In Europe, any statement advertising effect of nutrients on dis-ease risk reduction and treatment is strictlyregulated under article 14.1a of the health claims regulation(http://www.efsa.europa.eu/en/topics/topic/nutrition.htm?utm_source¼%20homepage&utm_medium¼infocus&utm_campaign¼healthclaimshttp://www.efsa.europa.eu/en/topics/topic/nutrition.htm?utm_source¼homepage&utm_medium¼infocus&utm_campaign¼healthclaims). Recently, the Euro-pean Food Safety Authority (EFSA)e the risk assessment au-thority for food and feed safety in the European Union e hasreleased guidelines on scientific assessment of health claims,which enforces food manufacturers to show the quality, rele-vance and adequacy of studies supporting the health claim(Vero & Gasbarrini, 2012). Currently efforts are underway toset best practice guidelines for health claim dossiers in Europe,for example through the EU funded BACCHUS project, whichis specifically funded to provide good quality evidence forhealth claims on polyphenols, bioactive peptides and cardio-vascular outcomes (www.bacchus-fp7.eu).
In contrast to these challenges, however, significant op-portunities for the food industry emerge that can not beignored. Disease prevention through healthy nutrition is apriority on the political agenda of many countries andthis is a clear opportunity for the food industry to claimmore market share than the pharma industry in this area.
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development, Trends in Food Science & Technology (2014), http://dx.doi.org/1
Food and beverage companies that seek to enter the marketof functional foods for health and wellness recognize theneed for investment in new research and development(R&D) competencies. The food industry has been tradition-ally regarded as a sector with low R&D-to-research ratioand little innovation (Bigliardi et al., 2013). But, with theintroduction of high-throughput technologies e primarilynutrigenomics e to food research, the situation has changedand now the grand challenge is integration of findingsacross multiple research disciplines in food science (Khoo& Knorr, 2014). For instance, the giant food companyNestl�e has established its own “Institute of Health Sci-ences” in 2011 with focus on “integrated systems science”.However, most of food and beverage companies e particu-larly small and middle size manufacturers-need R&D stra-tegies that can support substantiation of health claimsassociated to bioactive ingredients in an integrative manner.The food industry can take advantage of valuable experi-ences that the pharma industry has gained during years ofheavy investment in technology development and scientificresearch for tackling complexity of human diseases. Ofcourse, due to differences between a drug (with an immedi-ate health effect) and a functional food ingredient (with along-term health effect), this does not mean that pharma-ceutical standards should be directly applied to the food in-dustry. Nevertheless, considerable similarities betweenpharmaceutical and nutraceutical production pipelines interms of addressing purity, safety and efficacy imply thatalready existing and tested technological platforms in thepharmaceutical sector could be e at least partially e adop-ted and tailored to the needs of the food industry (Hardy,Hardy, & McElroy, 2002). For example, knowledge man-agement and systems modeling technologies, which havebeen extensively used e in an integrated manner e acrossall levels of pharmaceutical production pipeline, could playa similar role in support of knowledge generation for devel-opment of new functional food products.
Unlike the pharmaceutical industry that has establisheda firmly strong technological infrastructure to deal withthe complexities stemming from the drugedisease rela-tions, the food industry appears to lag behind such advance-ments when it comes to exploring dietedisease relation andproving safety and efficacy of functional ingredients. Thisis because food e compared to drug e comprises of a largespectrum of molecules that elicit numerous physiologicalresponses and, due to this complexity, nutritional sciencehas been long lagging behind advances in pharmacology(Verg�eres, 2013). The pharmaceutical industry has wit-nessed a gradual transformation from a manufacturing-based to a knowledge-based industry, highlighting theincreasingly important role of knowledge-driven systemsbiology in support of time- and cost-effective decision mak-ing (Butcher, Berg, & Kunkel, 2004). Systems biology ap-proaches in the pharmaceutical R&D attempt to model andpredict drug safety and efficacy across multiple biologicalscales e from molecules to cells, tissues and organs e by
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integrating large amounts of experimental and literaturedata (Fig. 1). The ultimate goal is to find biological path-ways influenced by candidate drugs, interpret the possibleeffects of drugs on the disease mechanism, and predictthe beneficial clinical outcome of candidate drugs. Thereare several examples of successful application of systemsbiology to drug discovery efforts (Henney, 2009). To high-light the importance of systems modeling approaches in thepharmaceutical NPD, the FDA’s Center for Drug Evalua-tion and Research (CDER) issued a report in 2011 empha-sizing on the value and utility of systems modeling as partof its review (http://www.fda.gov/downloads/Drugs/ScienceResearch/UCM264594.pdf).
Systems biology is an emerging discipline in the field ofnutraceuticals and functional foods that promises to in-crease our understanding of how food ingredients influencebiological pathways and intervene with disease processes(Panagiotou & Nielsen, 2009). Although the idea ofapplying systems biology methods to human nutritional sci-ences has been advocated in the literature for some time(Corth�esy-Theulaz et al., 2005; Shetty & McCue, 2003;Van Ommen & Stierum, 2002), this concept has beendisconnected from the substantiation of health claims forfunctional foods (e.g. Annunziata & Vecchio, 2011;Lalor, Madden, McKenzie, & Wall, 2011; Pothoulaki &Chryssochoidis, 2009). To the best of our knowledge, thereis no suggestion in the published literature how systems-based technologies could be applied to substantiating healthclaims within the frame of an integrated product develop-ment strategy.
Fig. 1. Integrative knowledge- and data-driven modeling of complex human bbiomarker discovery in the p
Please cite this article in press as: Younesi, E., & Ayseli, M. T., An integrated s
development, Trends in Food Science & Technology (2014), http://dx.doi.org/1
To roughly demonstrate the current gap in the field ofsystems biology between pharmaceutical and foodresearch, we searched PubMed (www.ncbi.nlm.nih.gov/pubmed) using the Advanced Search facility for systemsbiology studies that are conducted in both pharma andfood domains. Table 1 summarizes queries (at a comparablelevel) and results (accessed on 12.02.2014). As expected,the number of published papers reporting systems-basedapproaches in drug discovery and development is fargreater than those published in functional fooddevelopment.
This knowledge gap implies that the food industryshould quicken the pace to take up and integrate systems-based technologies into their production pipeline. Accord-ingly, we propose a strategy based upon which systemsbiology advancements in the pharmaceutical industry canbe adapted for supporting health claims in the functionalfood sector.
Integrated systems-based NPD as a new model forfunctional food development
At present, health claims regulations are in place in mostdeveloped countries but there are no universal regulationsfor nutraceuticals and thus, varying regulatory approachesare enforced in different countries (Bagchi, 2006). Despiteestablished systems that are in use for the approval ofhealth claims in developed countries, different agencieshave different views on efficacy claims, employingdifferent standards for levels of scientific evidence, andeven different processes for evaluation of such claims(Lalor & Wall, 2011). Due to these differences,
iology. This schema represents the state-of-the-art approach to drug andharmaceutical industry.
ystems-based model for substantiation of health claims in functional food
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Table 1. Comparative analysis of published papers on systemsbiology in pharma and food research.
Domain Query No. retrievedarticles
Food (“functional food”) AND“systems biology”
3
Food (“nutraceutical”) AND“systems biology”
6
Food (“nutrigenomics”) AND“systems biology”
39
Pharma (“drug”) AND “systemsbiology”
2860
Pharma (“pharmaceutical”) AND“systems biology”
376
Pharma (“pharmacogenomics”)AND “systems biology”
77
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nutraceuticals do not face the same level of scrutiny aspharmaceuticals in regards to product claims and intendeduse, which may lead to products of variable quality andwith claims of questionable merit. For instance, a reportby FDA showed food supplement recalls preceded drug re-calls over a period of 9 years (Harel, Harel, Wald,Mamdani, & Bell, 2013). Accordingly, in the absence ofa flexible, universal strategy defining the minimum require-ments for substantiation of health claims, the rate of healthclaim failures will remain high. Although in earlier timesevaluation of health claims only required proofs from scien-tific evidence based on association between a food and aneffect, as defined by PASSCLAIM criteria (Aggett et al.,2005), EFSA currently places particular emphasis onconclusive cause-and-effect evidence from randomizedclinical trials (Mitchell, Aggett, Richardson, & Stowell,2011). To remain competitive in the market, food com-panies need to satisfy the regulatory requirements for theirhealth claims. However, the prerequisite for their success isdevelopment of technologies that support innovation, pat-enting and design of clinical studies at large scale (Mark-Herbert, 2004). Currently, for most of dietary supplementsin the market such as probiotics, FDA has not approvedany health claims, indicative of insufficient strong scientificevidence for these products (http://nccam.nih.gov/health/probiotics/introduction.htmhttp://nccam.nih.gov/health/probiotics/introduction.htm). Moreover, between2012 and 2013, the FDA issued a record number ofwarning letters to marketers of food products about illegalclaims made on supplement labels (www.fda.gov/iceci/enforcementactions/WarningLetters/default.htm). In late2012, the Inspector General of the US Department ofHealth and Human Services reported that many supplementcompanies make unsubstantiated health claims on their la-bels and do not comply with law (https://oig.hhs.gov/oei/reports/oei-01-11-00210.asp). Indeed, an established sys-tems biology strategy e in the overall food NPD pipelinee to biologically explain and scientifically support the dis-ease- or risk-modifying effects of food ingredients could
Please cite this article in press as: Younesi, E., & Ayseli, M. T., An integrated s
development, Trends in Food Science & Technology (2014), http://dx.doi.org/1
significantly accelerate and support the substantiation pro-cess for development of new functional food products.
Among a few functional products to successfully passthrough the regulatory screening, Fruitflow is a successfulexample with well-substantiated health claims. The mainclaim to reduce platelet aggregation and facilitate blood cir-culation was supported by several clinical trials (e.g.O’Kennedy, Crosbie, Lieshout, et al., 2006; O’Kennedy,Crosbie, Whelan, et al., 2006b). Early planning for productdevelopment and clinical trials has been mentioned as thekey factor to success of this functional product(O’Connor, 2013). Here, the challenge would be to engagewith expensive basic research and risky clinical trials toprovide enough scientific evidence supporting the link be-tween bioactive ingredients and a decreased incidence ofchronic disease. Platelet aggregation mechanism and path-ways involved in blood clot are known since the discoveryof Aspirin ingredient in 1763 and its synthesis as drug in1897. However, it was after almost three decades that theidea of finding a natural bioactive ingredient with similarmode-of-action in fruits and vegetables led to identificationof potent platelet inhibitors in tomato extract (Dutta-Roy,Crosbie, & Gordon, 2001). The long interval from theconception of this idea to first-in-human clinical trials in2006 implies that the published knowledge on platelet in-hibitors such as Aspirin, thrombosis and their underlyingpathways between 1986 and 1999 could have beencollected and consolidated into an abstract model andfurther enriched and validated by fresh experimental datawith the aid of systems-based approaches so that themode-of-action would have been predicted much earlierand clinical trials could have been designed in a moreinformed and objective way.
To this end, we propose that systems biology approacheshave the potential to reduce the time and cost of functionalNPD by two means:
� model-based discovery of molecular targets and bio-markers linked to bioactive ingredients in the contextof disease mechanism, and
� evidence-based substantiation of functional ingredientsthrough linking the ingredients mode of action to theirexpected health effects.
This strategy, which is currently experiencing a fastdevelopment and application in the pharmaceutical sector,takes advantage of integrating both knowledge- and data-driven methods through mechanistic modeling of healthproblems (Younesi & Hofmann-Apitius, 2014). In thisway, a cause-and-effect relationship between ingredient inquestion and expected health claim can be establishedand the mode of action of ingredient e at the mechanisticlevel e can be supported by solid scientific evidence atthe clinical level. The authors foresee that application ofthis strategy to the field of functional food can enhanceR&D competencies of the food industry to implement a
ystems-based model for substantiation of health claims in functional food
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Fig. 2. Proposed integrated systems-driven NPD. The proposed strategy provides an integrated view on the product development life cycle, therebyincreasing efficiency in time and costs, and supporting informed decision-making.
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more integrated NPD pipeline with predictable health out-comes (Fig. 2).
ConclusionsWith the advent of high-throughput technologies and
their application to the food science, the food and beverageindustry has been taking steps to transform its traditionalR&D and product development process into a knowledge-based robust pipeline that can fully support developmentof functional products based on sound science. This evolu-tion has already been underway in larger companies butneeds to be adopted by other manufacturers intending todevelop functional products. As a consequence, the foodand beverage industry is facing with a situation in whichthey must quickly adapt to new market demands and regu-latory updates and be prepared to make expensive and riskydecisions as to whether proceed with significant invest-ments on development of functional products, all the wayfrom the basic research to conducting clinical trials.Thus, decisions on development of new functional productswith intended health claims by food manufacturers requireconcrete scientific criteria. To accurately meet the currentlevel of stringent regulations for functional products, thefood industry needs to tackle this problem through integra-tive approaches. Multidisciplinary integration of complexbiological knowledge relevant to human health and diseaseinto the functional product development process not onlycan increase the capacity of innovative product develop-ment but also can support informed decision-making.
Although the systems biology strategy proposed here isstill evolving in the nutraceutical industry, it is alreadycontributing to meaningful decisions in drug discoverybusiness by providing rapid characterization and interpreta-tion of disease-relevant responses. Systems-based ap-proaches have the potential to provide added value to theexisting standards in the functional food research byconsolidating scattered knowledge and data, supportingtranslational research by early predictions on the viabilityof expected health effects, and ultimately increasing theresolution of foodehealth relationships by linking molecu-lar mechanisms to health outcomes across multiple
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biological scales and data layers. In conclusion, adoptionof learned lessons from the pharma industry by food andbeverage businesses can accelerate their evolution in areasonable pace with the ultimate aim of going beyondfood fortification and making food functional.
AcknowledgmentsThe authors wish to thank Dr. Simin Homaeipour for
support in writing and critical reading of the manuscript.
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