Probiotics - Discussion Paper

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Report submitted to the Natural Health Products Directorate, Health Canada

March 2005

Nutritech Consulting
Winnipeg, Manitoba
Prepared by: K.C. Fitzpatrick

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Executive Summary

The focus of this discussion paper is probiotics which have been defined as live microorganisms that when ingested in appropriate quantities, have a beneficial effect in the prevention and treatment of specific medical conditions by improving the host's intestinal microbial balance¹. The Natural Health Products (NHP) Regulations define a probiotic as a monoculture or mixed-culture of live micro-organisms that benefit the microbiota indigenous to humans². A probiotic is limited to non-pathogenic microorganisms.

An extensive internet search was conducted and thirty interviews were initiated with researchers across Canada . The results of eight are summarized in this report as is information taken from internet searches of individual researcher profiles. It was often difficult to determine from website information whether the research involved a focus on Natural Health Products (NHP) and/or functional foods. Attempts to clarify this through contact with the individual researchers by email and telephone interviewing were for the most part unsuccessful.

Key Themes and Suggested Next Steps

The following are identified as priority areas in the probiotic area by the NHP Directorate (NHPD) and the NHP Research program (NHPRP). It must be emphasized that these issues are the result of a very limited sampling of the probiotic research community and are meant to serve as a starting point for further consultations.

1. The need for further consultation and dialogue

An interesting finding of this project was that many of those involved in probiotic research specifically in the NHP area (i.e. not food or animal health) are medical doctors and clinicians. This appears to be unique in research involving bioactives commonly thought of as 'nutraceuticals' - that is ingredients from plants or animals with medicinal properties.

Of those affiliated with academic faculties outside of medicine, many are working in close collaboration with a medical professional, who is usually a gastroenterologist. Also, many are biomedical researchers or are physicians themselves. In this project, there was a challenge in communicating with the probiotic community focused in the medical field, and obtaining good information, as there was a general lack of response to interview requests. It can be noted as well that, from the information gathered in this project, it is difficult to determine what, if anything, the NHPD and the NHPRP can offer the medical doctor or physician involved in probiotic research. Thus further attempts at dialogue between the probiotic research community and the NHPD are required. The involvement of key researchers affiliated with the prominent probiotic research centres and clusters is also encouraged in any follow-up activities.

2. Greater interactions between probiotic researchers and the medical community

As noted, the diverse nature of the probiotic research community became apparent in this project. Research streams appear to be focused on activities which have a more agricultural base versus those which have greater biomedical and clinical application. The need to build partnerships and better coordinate research between these two areas will be important in the future in order to further build Canadian research capacity in probiotics. Mechanisms should be established to provide more opportunities for interactions between the two research communities as well as with scientists involved in other areas of NHPs in order to encourage synergies of common activities to avoid duplication.

A joint conference possibly hosted by the NHP Research Society and the AFMNet with the focus being aligning these two groups and providing the venue for networking and scientific exchanges is one suggestion. Such a conference would be similar to the two highly successful events hosted by the NHP Research Society, but more broadly based. Another suggestion would be to host a series of regional workshops.

3. Need for NHPRP information sessions

There appears to be a very significant lack of awareness among probiotic scientists and the medical community involved in probiotic research regarding the NHPD, the NHP Regulations and the NHPRP, including the partnership program with the Canadian Institutes of Health Research (CIHR). It is recommended that any consultations that the NHPD may undertake with the probiotic research community include an overview of the NHPD, the NHP Regulations and the research priorities of the NHPRP. In addition, information should be provided regarding how the partnership program with CIHR operates. Although it is recognized that this partnership program only began this year, it would be of value for the NHPD to provide informational workshops to the probiotic and NHP research community.

4. Mechanisms to support funding of probiotic research

Support for research in the application of probiotics and NHPs as alternatives to conventional health care was identified as a priority with an emphasis on the need for specific funding mechanisms. Funding directed to probiotic research is a relatively new area. Researchers are now seeking funds from 'conventional' sources such as the CIHR, the National Sciences and Engineering Research Council (NSERC), industry associations and increasingly from the industry. Most importantly, it was noted that the involvement of the medical community makes it more difficult for 'conventional NHP researchers' (i.e. those whose affiliation is not strictly with a medical faculty or who have not been involved in research related to pharmaceuticals, for example) to secure when the competition includes physicians.

There has been a reduction in direct funding and 100% grant programs over the past decade, and an increase in the number of partnership programs with higher funding success rates (examples include industry associations and provincial funding) compared to investigator-initiated grants (i.e. through agencies such as CIHR). This concern was especially noted among those researchers with stronger ties to the agriculture or nutrition areas (i.e. as opposed to medicine) as well as those who are not funded to any significant degree by industry - several of whom were the same people.

Encouraging the continued funding support for probiotic research through Industry associations such as the Dairy Farmers and provincial agriculture and health departments is important as often this funding is for smaller scale research that is conducted as 'proof of concept' to accumulate the necessary data for submission to granting agencies such as CIHR. This data is often also required to leverage industry dollars for larger scale research. Additional funding from such sources could be encouraged through matching programs whereby the industry association and the government agency (federal and/or provincial) could each provide 50:50 funding.

In addition, industry research initiatives should be encouraged. A potential model is Agriculture and Agri-Food Canada (AAFC)'s Matching Investment Initiative Program (described in Appendix D of this report) where industry and AAFC match funding for AAFC directed research projects conducted on behalf of the industry. Perhaps this type of model could be explored as a way to establish partnership funding mechanisms from industry, association(s), provincial and federal sources overall for university health related research in NHPs.

Conclusion

This discussion paper identified an extensive and sophisticated scientific community actively involved in probiotic research in Canada . Probiotic research is being conducted to various extents across the country with Alberta having more focus on dairy based probiotics (mostly for animal health and foods) and the Eastern regions of the country conducting a significant amount of research in all aspects of probiotics for NHPs, food and animal health. In addition, four very strong research hubs exist in Eastern Canada (Canadian Research and Development Centre For Probiotics, McGill University , Institute for Functional Foods and Nutraceuticals (INAF), and Agriculture and Agri-Food Canada, St. Hyacinthe ) . Research activities are very comprehensive with many areas of health and disease conditions being studied at both the basic and applied levels.

Four broad topics and issues related to conducting probiotic research in Canada and with significance to the NHPD, the NHP Regulations and the NHPRP were identified as areas that could be explored further through consultations with the probiotic research community. Involvement of 'non-traditional' key funders identified in this paper - industry associations and provincial agriculture and health departments, is essential to ensure that such funding is maintained, and if possible increased, that dialogue continues and ties between all stakeholders are strengthened further. It is recommended that these funders are invited to any future consultations to explore ways to further support funding in this area. The involvement of key researchers affiliated with the prominent probiotic research centres and clusters is also encouraged in any follow-up activities.

Table of Contents

• Introduction
• Perspectives on Natural Health Products - Stakeholder Consultation, 2001-2002
• Overview of Natural Health Products Regulations
• The Natural Health Products Research Program
• Probiotics as Natural Health Products
• Probiotics in the Self-Care Continuum
• Probiotic Research in Canada
• Key Probiotic Clusters in Canada
• General Observations
• Key Themes and Suggested Next Steps
• Conclusion
• Appendix A - Probiotic Researcher Interview List
• Appendix B - Probiotic Research Questionnaire
• Appendix C - Probiotic Researcher Database
• Appendix D - Probiotic Funding Agencies

Introduction

In March of 1999, on the recommendation of the Standing Committee on Health, the Office of Natural Health Products (NHP), now the Natural Health Products Directorate (NHPD) was created. The mission statement of the NHPD is to ensure that all Canadians have ready access to NHPs that are safe, effective, and of high quality, while respecting freedom of choice and philosophical and cultural diversity.

With the enactment of the Natural Health ProductRegulations (NHP Regulations) in January 2004, the NHP category is legally recognized within the Canada Food and Drug Act as a special sub-section of drugs³. NHPs are defined in the Regulations as vitamins and minerals, herbal remedies, homeopathic medicines, traditional medicines, probiotics, and other products like amino acids and probiotics, and that are used to diagnose, treat and/or prevent disease, restore or correct function or maintain or promote health. This definition includes "nutraceuticals" that were originally proposed by Health Canada in 1998 to be "a product that has been isolated or purified from foods and generally sold in medicinal forms not usually associated with food. Nutraceuticals have been shown to exhibit a physiological benefit or provide protection against chronic disease"⁴. Even though not explicitly identified as a part of the definition for NHPs, these products are assumed to be available to consumers in "dosage form" as capsules, pills, tablets or in liquid form and not to include products in a food medium⁵.

The focus of this discussion paper is Probiotics, defined as live microorganisms that when ingested in appropriate quantities, have a beneficial effect in the prevention and treatment of specific medical conditions by improving the host's intestinal microbial balance⁶ and are available to consumers in capsules or supplements that are commonly sold in a medicinal or "dosage" form. Until the enactment of the NHP Regulations, probiotic supplements were considered as 'nutraceuticals' and confusion still exists as to their regulation as probiotics within the probiotic research community. Specific emphasis is given in this paper to an overview of Canadian probiotic research and issues related to conducting probiotic research in Canada . Although the development of technologies and the use of probiotics in conventional foods (as 'functional foods') is a very important area for both researchers and industry, a discussion of this topic is not included as it does not relate directly to NHP Regulations or the NHP Research Program (NHPRP).

An extensive internet search was conducted to ensure that the majority of probiotic researchers were captured for a Canadian database. In total, fifty-five researchers involved in NHP research consistent to that defined in the NHP Regulations are included. It was often difficult to determine from website information whether the research involved a focus upon NHP and/or functional foods. Attempts to clarify this through contact with the individual researchers by email and telephone interviewing were for the most part unsuccessful.

Nine of the most prominent probiotic researchers are highlighted in the database. It is recommended that the NHPD invite these individuals to any future consultations.

Perspectives on Natural Health Products - Stakeholder Consultation, 2001-2002

Over the period of 2001-03, a series of consultations were held which resulted in four central themes that served as cornerstones in the development of the NHP Regulations framework and the NHP Research Program: Quality and Safety; Research; Population Groups and Issue Areas; and Information, Informed Choice and Utilization⁷. Recommendations relevant to research priority setting in each of these four areas, where relevant, are briefly described.

1. Quality and Safety

Since many Canadians use NHPs in the management of their health, ensuring that these products are safe, effective and of high quality was a key area of discussion during the consultation process.

Drug Interactions with Natural Health Products - Interactions between NHPs and pharmaceutical drugs (both their positive and negative effects), in particular, biomedical, clinical and epidemiological research on NHP-drug interactions and research related to reporting, dissemination and use of information about interactions were identified during stakeholder consultations as important research foci for the NHPD.

Quality Controls and Product Standards - The crucial goal of establishing standards of the quality and safety of NHPs was examined. Research priorities including the d evelopment of methods for assessing botanical identity; the establishment of information and information dissemination related to purity specifications; the identification and development of reference materials; the development of analytical methods to determine markers, to evaluate and identify biologically active components, and methods to monitor outcomes were identified.

2. Research

Building Complementary and Alternative Health Care (CAHC) and Natural Health Products Research Networks - The need to network and to develop formal or informal networks in order to create and transfer knowledge, encourage research uptake, and build research capacity between the areas of CAHC and NHPs has been emphasized. The development of a conceptual framework; a national CAHC/NHP network, possibly consisting of different types of networks; and external relationships with the government, funding agencies and existing networks, was recommended.

3. Population Groups and Issue Areas

The Role of Natural Health Products and Complementary and Alternative Health Care in HIV/AIDS - Developing a Research Agenda - identified research priorities concerning the use of NHPs and CAHC with regard to individuals with HIV/AIDS including research on beneficial and detrimental interactions among NHPs and interactions between NHPs and drugs used by people with HIV/AIDS; focus on NHPs used in treatment and support of HIV/AIDS-related conditions and prioritization of the NHPs to be researched first. Research to advance integration across the continuum of health care practices and services, with a special focus on CAHC and NHPs were also emphasized, including the need to build research capacity, develop standards of evidence and research skills, build partnerships, explore opportunities and increase the profile of CAHC and NHPs in existing HIV/AIDS networks and programs.

Natural Health Products Research in Children and Youth: A Priority-Setting Conference - reported recommendations including the creation of a usage database and evaluate current data on NHPs, explore both basic and clinical science issues to identify gaps in knowledge of NHPs and children and youth; set priorities for knowledge translation and transfer to consumers and research ethical questions related to the healthcare of children and research methodologies for the study of NHP use in children.

4. Information, Informed Choice and Utilization

The fundamental importance of the ability of Canadians - both the general public as well as health care professionals - to make informed choices concerning the use of NHPs was examined through several consultations. Information and Informed Choice in the Use of CAHC and NHP: An Invitational Roundtable detailed the challenges in this area. Key legal and ethical issues related to NHPs and CAHC were explored in Health Law and Ethics in Relation to the Use of CAHC and NHP: An Invitational Roundtable. Further discussion on health law and ethics issues and on current initiatives in this area is presented in Reflections on Health Law and Ethics in CAHC. Information and informed choice issues concerning health care practitioners as well as the public are addressed in Reflections on Education, Information and Informed Choice in CAHCe. Information currently available on CAHC in the context of initiatives to gather data on the health of Canadians and on health care in Canada is presented in CAHC - Current Status and Future Development: A Discussion Paper.

Overview of the Natural Health Products Regulations

The NHP Regulations⁸ include provisions on definitions, product licensing, site licensing, good manufacturing practices, clinical trials, labeling and packaging requirements, and adverse reaction reporting. The Regulations came into force on January 1, 2004 and provide for a transitional period that will span from 2 to 6 years (2 years for site licensing and 6 years for products with Drug Identification Numbers (DIN).

The definitions include the definition of a natural health product (including, for example, vitamins, minerals, herbal remedies and homeopathic medicines) and other terms (recommended conditions of use, adverse reaction, etc.). All licensed products must display a product identification number issued once a product is authorized for sale in Canada by the NHPD. Product authorization requires either: I) reference to a NHP monograph, or ii) submission of other evidence of the safety and health claim. All monographs developed for NHP ingredients to date have been based on the requests from Industry. The monographs that have been developed are accessible on the NHPD website⁹. Product licence applicants may cite these monographs to support the safety and efficacy of the probiotic ingredients in their product.

Site licensing requires that all manufacturers, packagers, labelers, and importers be licensed; sites have procedures in place respecting distribution records and product recalls; where applicable, sites have procedures in place for the handling, storage and delivery of their products, and sites meet good manufacturing practice requirements (GMPs). GMPs are to be employed to ensure product safety and quality, and include standards and practices regarding all stages of product manufacture. Standard labeling requirements are established to ensure consumers can make informed choices. An adverse reaction reporting system requires product licence holders to monitor all adverse reactions associated with their product and to report serious adverse reactions to Health Canada.

Clinical trials conducted in Canada using NHPs are also subject to the NHP Regulations and thus such research conducted on Probiotics falls within the mandate of the NHPD. A clinical trial is an investigation of an NHP that involves human subjects and that is intended to discover or verify the product's clinical, pharmacological or pharmacodynamic effects, to identify any adverse events that are related to its use, to study its absorption, distribution, metabolism and excretion, and to ascertain its safety or efficacy. The clinical trial sponsor is responsible for applying for clinical trial approval from the NHPD, and research ethics approval from an independent research ethics board.

Evidence from clinical studies provides valuable information about the efficacy and safety of probiotics. Clinical studies identified by the NHPD that probiotic researchers across Canada have expertise in conducting include the following:

• systematic reviews, such as meta-analyses of randomized controlled trials or other trials;
• randomized controlled trials (preferably multicentred);
• studies without randomization and/or control groups; and
• non-experimental observational studies, such as epidemiological, cohort studies, or case-control studies.

The NHP Regulations set out obligations for the clinical trial sponsor, which include good clinical practices, product labeling, record keeping, information and samples submission, and adverse reaction reporting. The site licence provisions do not apply to clinical trials, and sponsors are not required to have a site licence to conduct a clinical trial. Health Canada inspects clinical trial sites for compliance with good clinical practices. The NHPD is in the process of finalizing the necessary guidance document and forms on clinical trials. In the meantime, as clinical trial requirements are very similar to those required for drugs, the Therapeutic Products Directorate (TPD) guidance documents and forms are being accepted as per TPD requirements.

Researchers conducting pre-clinical trials with the primary focus on accumulating evidence supporting safety and efficacy of probiotics must also be aware of the NHP Regulations. Pre-clinical studies involving in vitro and in vivo studies (e.g. animal studies) can provide valuable information to the NHPD in their assessment of a novel probiotic product.

The Natural Health Products Research Program

As part of its recommendations, the Standing Committee on Health also identified the need for more focused research in NHPs. On April 1^st, 2003 , the NHPD launched the Natural Health Products Research Program (NHPRP)¹⁰. Over the next five years, as approved by the Treasury Board, the NHPRP will provide $5 million to support NHP research with $2 million dollars allocated to a partnership with the Canadian Institutes of Health Research (CIHR). The NHPRP supports projects through g rants, contributions and operating funds. The primary interest of the NHPRP is to support product based rather than practice based projects. Thus, for example, proposals exploring complementary and alternative health care (CAHC) must have a significant focus on NHP research.

Probiotics as Natural Health Products

Probiotics

It has been nearly a century since Metchnikoff postulated that lactic acid bacteria offered health benefits leading to health and longevity¹¹. Since that time, the concept of probiotics has advanced dramatically¹² and probiotics are becoming an increasingly important functional food and NHP.

Probiotics have been defined as live microorganisms that when ingested in appropriate quantities, have a beneficial effect in the prevention and treatment of specific medical conditions by improving the host's intestinal microbial balance¹³. These microorganisms are believed to exert biological effects through colonization resistance, whereby the indigenous anaerobic flora limits the concentration of potentially harmful (mostly aerobic) germs in the digestive tract. Other modes of action, such as supplying enzymes or influencing enzyme activity in the gastrointestinal tract, may also account for some of the other functions that have been attributed to probiotics.

Promising probiotic strains include members of the genera Lactobacillus, Bifidobacterium, and Enetrococcus and the species of most interest for efficacy testing and in the market include Lactobacillus acidophiulus, L. johnsonii, L. Casei, L. gasseri, L. plantarum, L. rhamnosus, Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium infantis, Enterococcus faecalis and Enterococcus faecium¹⁴.

Among the accepted criteria for isolating and defining probiotic bacteria¹⁵ are:

• Human origin;
• Resistance to acidity and bile toxicity;
• Adherence to human intestinal cells;
• Colonization (even transiently) of the human gut;
• Antagonism against pathogenic bacteria;
• Production of antimicrobal substances;
• Immune modulation properties;
• Clinically proven health effects (dose-response data); and
• History of safe use in humans.

Probiotics in health maintenance and disease prevention

Probiotics have been investigated in relation to a number of health concerns, including atopic eczema¹⁶, vaginal yeast infections¹⁷, rheumatoid arthritis¹⁸ and liver cirrhosis¹⁹. Although there is some clinical evidence for the role of probiotics in lowering cholesterol, the results are conflicting²⁰. The greatest clinical evidence for probiotic use is related to its use in improving gut health and stimulating immune function²¹.

Probiotics and improved gut function

The intestine is the body's most important immune function-related organ: approximately 60 % of the body's immune cells are present in the intestinal mucosa. The intestine also contains extensive microflora - 100,000 billion bacteria located mainly in the colon and comprising over 400 species of bacteria²².

Of the many functions of the intestine, immune functions are particularly important. The immune system prevents immune responses against dietary proteins - prevention of food allergies - and against pathogenic microorganisms, viruses (rotavirus, polio virus), bacteria (salmonella, listeria, clostridium, etc.) and parasites (toxoplasma) - prevention of chronic inflammatory diseases of the intestine.

Probiotics affect intestinal bacterial flora by increasing anaerobic bacteria and decreasing the population of potentially pathogenic microorganisms. This phenomenon can reduce the incidence of diarrhea, which is one of the most well recognized uses for probiotics and has been documented with a number of specific strains, including Lactobacillus GG, L. reuteri, Saccharomyces boulardii, Bifidobacteria species and others²³. Probiotics may also reduce the risk of colon cancer, likely due to their role in suppressing the activity of certain bacterial enzymes that may increase the levels of procarcinogens²⁴. Well-designed, randomized clinical studies are still required to define the role of probiotics as therapeutic agents in inflammatory bowel disease²⁵.

Probiotics and immune modulation

One of the putative effects of probiotics is the modulation of immune function. Specific cellular components in lactic acid bacteria strains seem to induce strong adjuvant effects including modulation of cell-mediated immune responses, augmentation of cytokine pathways and regulation of interleukins, and tumor necrosis factors. Probiotics such as Lactobacillus acidophilus and Bifidobacterium bifidum have been shown to influence select aspects of immune function involving one or several components of an immune response, e.g., humoral, cellular or nonspecific immunity. Although several in vitro and in vivo studies on probiotic effects on immunity have been reported, the specific mechanisms of the observed changes remain unclear and very few human intervention studies have been reported²⁶.

Some dietary substances, the so-called "prebiotics" can favor the growth of beneficial bacteria over that of harmful ones. The concept of prebiotics is relatively new and has recently been defined as nondigestible food ingredients that beneficially affect host health by selectively stimulating the growth and/or activity of bacteria in the colon²⁷ . The prebiotic, fructooligosaccharide (FOS), is found naturally in many foods, such as wheat, onions, bananas, honey, garlic, or leeks. They can also be isolated from chicory root or synthesized enzymatically from sucrose.

Fermentation of FOS in the colon results in a large number of physiologic effects including increasing the numbers of bifidobacteria in the colon, increasing calcium absorption, increasing fecal weight, shortening of gastrointestinal transit time, and possibly lowering blood lipid levels. The increase in bifidobacteria has been assumed to benefit human health by producing compounds to inhibit potential pathogens, by reducing blood ammonia levels, and by producing vitamins and digestive enzymes. A synbiotic productexerts both a prebiotic and probiotic effect.

NHP Approval of Probiotics

The NHP Regulations define a probiotic as a monoculture or mixed-culture of live micro-organisms that benefit the microbiota indigenous to humans²⁸. A probiotic is limited to non-pathogenic microorganisms. An example is Lactobacillus acidophilus.

Although the safety of traditional lactic acid bacteria is not in question, the more recent use of intestinal isolates of bacteria delivered in high numbers to consumers with potentially compromised health has raised the question of safety. Generally, the safety of lactobacilli and bifidobacteria has been reviewed and their pathogenic potential deemed to be quite low. This is based on the prevalence of these microbes in fermented food, as normal colonizers of the human body, and the low level of infection attributed to them²⁹.

Such toxicology and safety issues have been recognized within the NHP Regulations and the NHPD does require evaluation unique to probiotics . According to the Regulations , unlike other NHPs, conventional toxicology and safety evaluation is not sufficient to evaluate the safety of probiotic microorganisms as noted³⁰:

A probiotic is meant to survive or/and grow in order to benefit humans, which makes the use of these tests ineffective for probiotics. Therefore, a multi-disciplinary approach is necessary to examine the pathological, genetic, toxicological, immunological, gastro-enterological, and microbiological aspects of the safety of probiotic strains. These requirements were mainly based on AO/WHO's "Guidelines for the evaluation of probiotics in food-Report of a joint FAO/WHO working group on drafting guidelines for the evaluation of probiotics in food."³¹

Certain probiotic bacteria have been associated with human illnesses and/or have a high risk of developing antibiotic resistance and are not suited for use as probiotics. Products containing the following strains or species will be rejected as NHPs without further consideration:

• Bacillus cereus
• Bacillus clausii CNCM MA23/3V & CNCM MA66/4M
• Enterococcus spp.
• Bifidobacterium dentium
• Lactobacillus plantarum CNCM MA40/5B-p
• Parascardovia denticolens
• Pediococcus acidilactici CNCM MA28/6B
• Scardovia inopinata

Within the NHP Regulations, there are a number of safety considerations that must be addressed with regard to probiotics.

A. Antibiotic resistance profile

As with any bacteria, antibiotic resistance exists among some probiotic bacteria. The resistance may be related to chromosomal, transposon or plasmid genes. Bacteria containing transmissible resistance genes, especially to antibiotics important in human medicine, should not be used as probiotics.

B. Production of antibiotics

Bacterial strains confer resistance to antibiotics by producing enzymes that chemically modify structures of certain antibiotics; develop antibiotic resistance by mutation in the presence of the drug and may produce antibiotics. Such strains should not be used as probiotics.

C. Pathogenic potential

Organisms not commonly used or without a long history of use need to be tested for pathogenic potential and should be demonstrated to be free of virulent factors and toxin production. If the strain under evaluation belongs to a species with known hemolytic potential, determination of hemolytic activity is required.

D. Metabolic activities

Certain strains produce metabolites such as D-lactate and bile salt deconjugase which may cause problems in human physiology so these strains should not be used as probiotics.

Efficacy Considerations

As with other NHPs, pre-clinical experiments using animal models are encouraged before proceeding to human clinical trials. In order for probiotic strains to be efficacious, it is important for them to meet and maintain certain criteria, including minimum daily dose, acid and bile stability, intestinal mucosal adhesion properties, and viability throughout product shelf life. Special technologies are required to prevent loss of viability and may include freeze drying, selected excipients to control water activity, enteric coating for protection against gastric acidity and microencapsulation.

Dietary Recommendations for Probiotics

The amount of probiotics necessary to replenish the intestine varies according to the extent of microbial depletion and the presence of harmful bacteria. One to two billion viable organisms per day of acidophilus is considered to be the minimum amount for the healthy maintenance of intestinal microflora³².

Commercial Probiotic Products

Probiotic products were evaluated by the consultant during January and February 2005, at the following retail locations:

• Vancouver , BC - One natural health products independent merchandiser, One pharmacy
• Winnipeg , MB - One natural health products national chain, One pharmacy
• Toronto , ONT - One natural health products independent merchandiser, One pharmacy

Probiotics are available in various dosage forms, such as capsules, tablets, and powders. Overall, it was very surprising to see the lack of selection and availability of probiotic products in the Canadian retail market. Only three major brand labels were found at the national pharmaceutical chains and two at the NHP retailers. The NHP independent merchandiser stocked two of the national brands and one local label.

The probiotic products available in these locations as NHPs were identified as 'Probiotic complexes' containing either 5 or 6 Billion active strains, including the following:

• Lactobacillus Acidophilus
• Lactobacillus Bifidus
• Lactobacillus Rhamnosus
• Lactobacillus Salivarius
• Lactobacillus Bulgaris
• Lactobacillus Lactis
• Lactobacillus Casei
• Lactobacillus Brevis
• Bifidus longim
• Bifidus bifidum

The various strains were contained in the products in different percentages adding up to 100%.

The majority contained FOS - fructose oligosaccharides from chicory root as a prebiotic usually at the level of 60 micrograms. Label claims for FOS:
"FOS promotes reproduction and life of specific probiotics cultures".

Recommended intakes were one capsule daily for health maintenance and 2 - 3 capsules for therapeutic use. Prices ranged from $ 0.10 to $ 0.20 per capsule.

Standard Probiotic label information

None of the brands assessed carried DIN numbers. All products complied with the NHP Regulations as per supplying the product name, the quantity of product in the bottle, recommended conditions of use, including dosage form, route of administration, and recommended dose). The following cautionary statement appeared on one product:
"Probiotics are known to have a supportive interaction with nearly all types and classes of antibiotics. "

Two supplements specifically carried information regarding recommended use and purpose including:
"Recommended for individuals with lactose intolerance; travelers overseas; individuals being treated with antibiotics".

Other claims included:
"Restores the friendly bacteria found in a healthy digestive tract"
"Aids in digestion and absorption of nutrients"
"Promotes proper elimination of wastes"
"Super Strain"
"Supports intestinal and immune system health"
"For intestinal health"
"Higher potency"

Some products also included on the label various logos identifying "potency assured" or "purity assured".

All products did indicate that the number of 'active cells' were guaranteed at the time of manufacture.

One product label noted stability at room temperature but recommended refrigeration to safeguard the product from heat. One product of blister packaged capsules noted extra protection to the bacteria against moisture and oxygen.

Impact of processing, environment and diet on probiotic bacteria

Probiotics in NHPs and foods are fragile and particularly sensitive to processing conditions (such as freezing, drying, exposure to oxygen) and to storage conditions (such as room temperature, oxygen, moisture). In addition, a ccording to the NHP Regulations, another critical factor in successful therapy is the co-administration of a diet containing key growth factors for probiotic bacteria³³. For example, Lactobacilli require that a high milk or lactose content is incorporated in the diet, and products based on these bacteria should have labeling instruction for the special diet requirements. This indication did not appear on any of the product labels assessed by the consultant.

Quality Concerns

A significant quality issue for probiotic supplements is the viability of bacteria in the product, specifically how many organisms are alive when the consumer purchases it as many products claim only the amount at the time of manufacture. As well, the product should contain the bacterial species that it claims on the label, and potentially pathogenic microorganisms should not be present.

A recent Canadian study assessed whether commercially prepared probiotic products contained viable organisms, as claimed by the manufacturers, and particularly whether products labeled as containing Lactobacillus did so³⁴. An additional objective of the research was to identify and quantify as many species as feasible and to compare them with the contents listed on labels. The design was randomized, double-blind trial of 10 brands of probiotic preparations bought over-the-counter in British Columbia 's lower mainland. Only products claiming to contain Lactobacillus were included in the study. The study measured the viable organisms in each probiotic brand and quantities of Lactobacillus in each product.

The results showed that none of the 10 products tested matched their labeled microbiologic specifications and two brands grew nothing aerobically or anaerobically. No Lactobacillus grew in five brands, although their labels stated that this was the main species. Eight brands contained viable cells, but only 10% of the number stated by their manufacturers. Most product labels did not adequately identify or quantify microbes which led the author to conclude that the use of probiotics should not be recommended at this time.

In research conducted by a media outlet and broadcasted in 2003³⁵, two different probiotic capsules were each tested twice, including newly stocked retail product to determine the number of live bacteria and secondly near the end of the product's shelf life to test if the counts had fallen. The first label claimed 6 billion live cultures per capsule but testing showed only 1.7 billion and within two weeks, millions more bacteria died, with 460 million still alive. The second product did contain the label claim of more than one billion in the first test. But on the follow-up test, 692 million bacteria remained alive. Dr. Gregor Reid, director, Canadian Research and Development Centre for Probiotics, Lawson Health Research Institute, and professor of Microbiology and Immunology, University of Western Ontario , London was quoted on the program as stating "This is particularly disheartening, as you're getting a massive drop in viability, even within two weeks. You've picked two products but you could have picked 10 or 15 and, according to European studies, you'd find the same kind of results where you get a drop off in viability."

Research has further shown that products should contain between one million and one billion live bacteria to be efficacious³⁶. The media program concluded by stating that " ... manufacturers can say whatever they want on those containers. That's because there are no Canadian government regulations on how much live bacteria there should be, and no rules on what labels have to tell us about quantity".

Probiotics in the Self-Care Continuum

In developing the NHP Regulations, Health Canada 's intent was to regulate products that consumers can select and use themselves, without the need to consult a health care provider and obtain a prescription. According to the NHPD, self-care involves the activities individuals undertake for the prevention , treatment, and symptomatic relief of diseases, injuries or chronic conditions that individuals can recognize and manage on their own behalf, either independently or in participation of with a health care provider³⁷ . This includes the use of self-care products, such as NHPs and including Probiotic, that are safe, effective and of high quality.

The evidence applicants provide with the product licence application enables the NHPD to determine whether the NHP is or is not appropriate for self-care. Generally speaking, high quality probiotic supplements do not pose a risk when consumed at the levels recommended by responsible marketers and as indicated above.

Probiotics in Foods

Although not within the scope of the NHP Regulations definition of probiotics, it is important to note that in Canada , probiotic bacteria are also sold in foods almost exclusively in dairy products, capitalizing on the traditional association of lactic acid bacteria with fermented milk. Probiotic bacteria used in these products include various strains of Lactobacillus and Bifidobacterium . The dairy products associated with probiotic bacteria are primarily probiotic-added fluid milk and yogurt. Strategies for formulation of Canadian dairy products with probiotic bacteria are largely left up to the manufacturer.

Consumer awareness of Probiotics

Several of the researchers surveyed for this report commented on the lack of awareness of Canadian consumers regarding the health aspects of probiotics, which has resulted in a low market demand and a reduced ability to secure funding from the industry. Compared to the European probiotic market, which is dominated by probiotics in both food and supplement form, the Canadian market for these products is in its infancy. Consumers have been exposed to these ingredients mainly through yogurt consumption, but the term "probiotics" has yet to penetrate the Canadian vernacular.

One scientist indicated that communicating the importance of specific levels of bacteria to health professionals and then to consumers will prove beneficial for the Canadian market in the long run. "The medical community and dietitians are going to enhance awareness of this eventually but right now consumers don't have enough information to know if the food or supplement product they are consuming really is going to do for them what it needs to."

It was noted that the Canadian consumer does not really have an understanding of probiotics because there is little preexisting knowledge on which to build, such as traditional acceptance of the health benefits of certain bacteria in the diet. In Europe, the notion that yogurt is good for health is well established. Another issue is that the benefits being touted for probiotics are too general and not specific, such as the indications of St. John's Wort for depression and echinacea for colds. Consequently, to say probiotics provide immunity may be too vague for Canadian consumers.

However, it is anticipated that consumer understanding of probiotics will improve in the future, as the scientific base is built. The food industry appreciates such trends and in fact, in a recent Functional Foods Trends Survey conducted by Prepared Foods³⁸, probiotics moved from the No. 10 position it occupied in 2000 to No. 5 in 2003 in terms of growing importance in functional foods formulation efforts. According to MarketResearch.com³⁹ , the North American market for branded packaged cultured dairy products reached an estimated $5.9 billion in 2004, an increase of 7.9 percent on 2003. It predicts that it will reach $11.4 billion in 2009, with a compound annual growth rate of 14 percent.

An interesting area of novel food incorporation for probiotics in which a Canadian company is taking a lead in development includes chocolate bars. The stability of probiotics is currently a significant barrier to their use in non-dairy applications due to the effects that heat, humidity and other processing conditions have on bacteria. Montreal-based probiotics company  Lallemand, however, has developed technology to improve the stability of its coated probiotics in products ranging from chocolate bars to energy tablets. Foods that need to be baked, like cereal bars, require a higher level of protection, and technological issues still present problems when producing the finished product. Other foods being tested by several Canadian suppliers include infant formula and fruit juice. To date, though, no technology exists offering guaranteed stability across all strains and processes.

Probiotic Research in Canada

An extensive internet search was conducted to ensure that the majority of probiotic researchers were captured for a Canadian database. In total, fifty-five researchers involved in NHP research consistent to that defined in the NHP Regulations are included. It was often difficult to determine from website information whether the research involved a focus upon NHP and/or functional foods. Attempts to clarify this through contact with the individual researchers were for the most part unsuccessful.

Nine of the most prominent probiotic researchers are highlighted in the database. It is recommended that the NHPD invite these individuals to any future consultations.

Twenty eight interviews were initiated with researchers across Canada . The results were disappointing as it was very difficult to solicit interviews. This report summarizes the responses from eight researchers and also captures information taken from internet searches of individual researcher profiles. The interview list and questionnaire appear in Appendices A and B, respectively.

The lack of response to email and/or telephone interview requests by this particular research community was surprising. Despite numerous attempts, over twenty did not respond during a one month period. It is postulated that this may be due to the interesting finding in this project that many of those involved in probiotic research specifically in the NHP area (i.e. not food or animal health) are medical doctors who are may not be used to responding to these kinds of interviews or may not appreciate the value in participating in such a survey.

Overall, the results show probiotic research is being conducted to various extents across the country with Alberta having more focus on dairy based probiotics (mostly for animal health and foods) and the Eastern regions of the country conducting a significant amount of research in all aspects of probiotics for NHPs, food and animal health.

Research Activities

Information related to research activities was taken from internet searches of individual University and researcher profiles . In addition, participating researchers were asked to summarize his/her research in the area of probiotics. The detailed information appears in the Researcher database (Appendix C). As per the definition of NHPs, this discussion paper did not solicit specific information describing research activities in the area of foods, animal based human foods (such as dairy products) and animal health although it should be noted that these areas represent significant research activities in Canada. However, twenty-two of the researchers involved in animal based human food development, animal feed and animal health have been included in the database as the NHPD (or the Food Directorate of Health Canada ) may wish to contact these individuals at a later date. In addition, it is known to the consultant that many of these researchers anticipate working on probiotics for NHP use in the future.

As indicated above, an interesting finding in this project was that many of those involved in probiotic research specifically in the NHP area (i.e. not food or animal health) are medical doctors or food and nutrition researchers who have close collaborations with a medical professional, usually gastroenterologists. This may be due to the strong research focus in the probiotic area on gut health and gastro-intestinal disorders and diseases. Many researchers are assessing probiotics at a clinical level using out-patients or hospitalized populations.
In the NHP area (as opposed to foods), the two main research areas involve establishing more concrete scientific evidence and the development of more effective delivery forms for probiotics.

There appears to be a strong emphasis on conducting well-controlled clinical trials and determining how probiotic bacteria work in the human gut.

The importance of choosing appropriate strains at specific levels to yield a health benefit was emphasized. Research is also focusing on the definite mechanism of action for probiotics. There is also an increasing trend of combining strains to target specific health benefits. Dr. Jacques Goulet, scientific director, Institut Rosell, Montreal , Canada , suppliers of L b.acidophilus Rosell-52 and Lb. rhamnosus Rosell-11, has commented, "From a scientific point of view we are noticing that a single strain won't do the best job in improving health. Scientists are suggesting that probiotic supplements be a mixture of four, five and even eight strains to get the most benefit. The probiotic strains in these blends, however, should also be compatible because not all probiotic strains are and, therefore, may not yield the most beneficial effect."⁴⁰

Conditions Targeted for Probiotics

Much of the probiotic research being performed in Canada is very clinical in focus and involves the assessment of probiotic effects on immune cell function under various conditions. Research is attempting to determine the immunomodulatory properties that are specific to probiotic strains - recognizing that any one bacterial genus do not have the same immunomodulatory potential. Current research is also focusing on the use of probiotics in diarrhea, colon cancer (animal studies only), lactose digestion, immune system modulation, vaginal and urinary tract health, allergies, inflammatory disorders and hypertension.

Delivery And Dosage Issues

Defining dosage levels and maintaining viability in various delivery systems are an important research focus as probiotics are adversely affected by light, heat, oxygen and moisture. It was noted by one researcher that probiotic function is enhanced if consumed in a food environment, particularly within a dairy product. Dairy products provide an ideal medium in which these organisms can grow. However, with NHPs, determining whether or not the bioavailability of probiotics (that is, will they be alive once in the intestine and will they maintain viability) is an important research area. Protecting probiotics against stomach acidity to optimize survival and improving shelf stability are research areas in those laboratories that work closely with the industry.

Research regarding the dosage of bacteria to deliver a health or treatment effect is on-going. One scientist noted that, in general, colonization of microbes in the gut is easier to achieve at a lower dosage in food than with a supplement. This is because when bacteria are freeze-dried for a supplement, not all of the bacteria will survive and colonize so more bacteria may be required.

Areas of Expertise

The majority of probiotic researchers in the traditional health sciences area have conducted pre-clinical trials involving in vitro and in vivo studies (e.g. animal studies) prior to clinical studies in humans. Research activities encompass all health and disease related conditions, basic and applied.

The Canadian probiotic research community has expertise in clinical trials and conducts a wide range of studies including the following:

• systematic reviews, such as meta-analyses of randomized controlled trials or other trials;
• randomized controlled trials - several probiotic researchers are involved in multicentre trials and in research clusters, the most significant are described later in this section;
• studies without randomization and/or control groups; and
• non-experimental observational studies, such as epidemiological, cohort studies, or case-control studies.

Research activities focused on basic (that is mechanistic research at the cellular level) versus applied (that is focused upon human disease and health at an animal and human level) was quite consistent among the group. Most researchers surveyed indicated a focus of at least 50% on applied science. Those who identified the highest level and most consistent degree of funding success for human clinical studies were most active in the latter.

The individual researchers currently studying probiotics (in the agriculture, nutrition and medical fields) are well established in Canada. However, the majority of those interviewed have only been involved in the specific field of probiotic research for less than 10 years. This was also a trend apparent when the internet profiles of probiotic researchers not included in this survey were assessed. This is not surprising as the area of probiotic research, as well as industry and consumer interest, is a fairly recent phenomenon in North America , unlike in the EU where such products have been extensively studied and have been well accepted by consumers for several decades.

The number of publications in the probiotics area reflects the newness of the field in North America with publications ranging from less than 5 to around 20. Conference presentations were one venue noted by researchers as an important way to communicate their results.

Funding for Probiotic Research

Specific funding of probiotic research is a relatively new area. Funding was historically derived from the area of microbiology. Researchers are now seeking funds from 'conventional' sources such as the Canadian Institutes of Health Research (CIHR), the National Sciences and Engineering Research Council (NSERC), industry associations and increasingly from the industry. The competition for funding is becoming more intense as more researchers are interested in the study of probiotics. Most importantly, several researchers noted that the medical community are now becoming more interested and involved, making it more difficult to secure funds when the competition includes physicians.

Industry funding is difficult due to limitations in the areas of patenting and intellectual property. However, both national and international companies developing and marketing probiotic strains (see Appendix D) have provided funding to the Canadian research community.

Current funding for probiotic research for those not involved with industry is not significant, averaging $50,000 to $100,000 per year. Scientists who work extensively with industry quoted total funding for their programs in the range of $300,000 to over $2M in total. Most funds came from external sources, although internal (core) funding was identified as necessary for work in the clinical area.

Funding sources for probiotic research are identified in Appendix D. For the most part, these are the primary funding agencies for all Canadian NHP and nutraceutical research. The most important federal funding source identified by all those surveyed as well as that identified on websites is CIHR - it is viewed as the 'gold standard' and most prestigious of funds awarded for clinical and health research in Canada . NSERC is also a very important funder, especially in the area of biomedical research.

Over 50% of the individual scientists interviewed as well as the funding for Centers in this area have received matching funding from industry associations with the most important being Dairy Farmers of Canada. Provincial agencies that provide funding in agriculture and health also represent sources of matching dollars for probiotic research in Canada .

When submitting proposals to provincial funders and industry associations, most of those surveyed indicated an average funding success rate of about 50%, especially for projects emphasizing product development and with commercial potential. This was not the case with proposals submitted to federal granting agencies, especially CIHR and NSERC, where the success rate appears to be much lower except for those who were affiliated with a medical doctor or a health care facility.

It was noted by some that the area of probiotic research has limited patentability (i.e. "can't patent bacteria") and was the rationale as to why it was difficult to secure funding and why much research was focused on food use. However, as the example of London based Urex Biotech Inc. supports, patents and intellectual property specific to probiotic formulas, mixtures and complexes as well as delivery systems have been successful and are areas of research pursuit. There is a rising emphasis on intellectual property (IP) in order to engage industry partnerships, funding and licensing arrangements.

Key Probiotic Clusters

Canada is home to several well organized and prestigious research centres for probiotics that are recognized globally and have had both scientific and product development success in the area.

 Canadian Research and Development Centre For Probiotics (CRDCP)
(http://lriweb.sjhc.london.on.ca/LHRI/crdcp/who.html)

Located at the Lawson Health Research Institute's St. Joseph's Health Centre site in London Ontario, the CRDCP is made up of a group of basic and clinical scientists, and is linked to a number of researchers in Canada and internationally. The CRDCP is a unique and well funded research cluster located at Lawson Health Research Institute in London , Ontario . The more than twenty scientists affiliated with the Centre have cross- appointments at the Universities of Western Ontario (leading University) and Toronto . A listing of these researchers and their areas of focus is included in Appendix C. The centre also includes scientists from the University of Guelph and the Ottawa Hospital Research Institute.

The Centre's primary focus is to undertake basic discovery research on Lactobacilli and Bifidobacteria including studies in the areas of microbial ecology, proteomics, microbial genetics, biofilm studies, cell-signaling, immunology and population health. In particular, research focuses on women's health, premature infants and adults prone to or suffering from intestinal, urinary tract, wound and cardiovascular problems, as well as l ivestock studies designed to improve the well-being of the animals and replace the use of antibiotics in starter feeds. The centre's vision is to create an internationally recognized probiotic research centre that fosters the pursuit of excellent basic, discovery, and developmental and translational research leading to tangible benefits for both humans and animal.

Dr. Gregor Reid, director of the CRDCP, Lawson Health Research Institute, and professor of Microbiology and Immunology at University of Western Ontario has conducted a great deal of research producing strong evidence linking probiotics with the prevention of urogenital infections, and bladder and vaginal infections. As a result of Reid's work, the World Health organization requested that Reid and other international scientists develop guidelines for probiotics. Recently, this group established a probiotic code of conduct. In addition, Dr. Gregor Reid was awarded two US Patents: one along with Dr. Jeff Howard, Dr. Bing Gan and Dr. Andrew Bruce entitled "Treatment of microbial infections with bacterial proteins and peptides"; and another with Dr. Victor Han and Dr. Andrew Bruce on "Probiotic therapy for newborns". Both patents are issued to Urex Biotech Inc. (see below).

Recently, several researchers at the Centre have been awarded funding in the form of NSERC and CIHR grants to further their research in the area of probiotics or potential probiotic applications. Included are: Dr. John McCormick - 4 year grant from NSERC and 3 year grant from CIHR; Dr. Alan Bocking and Dr. Gregor Reid - 3 year grant from CIHR; Dr. Bing S. Gan and Dr. Jeff Howard - 3 year grant from CIHR; Dr. Mansel Griffith - had a Letter of Intent accepted by CIHR for studies on food safety; Dr. Keith Hayes - will be receiving significant support from the Rick Hansen Foundation; Dr. David Heinrichs - 3 year grant from CIHR; Dr. Quim Madrenas - Chosen to lead one of only five sites in the world for Clinical Immunology research; Dr. Miguel Valvano - 3 year grant from CIHR; and Dr. John Denstedt and Dr. Gregor Reid - 2 year grant from NIH in collaboration with Ixion, Florida.

To date, the following partners have made it possible to establish the Centre and organize its first international conference that was held on May 2nd, 2002: The Ontario Research and Development Challenge Fund; Abbott Laboratories; Canadian Institutes for Health Research (CIHR); Chr Hansen; Dairy Farmers of Canada; Kidney Foundation of Canada; Lawson Health Research Institute (LHRI); Natural Sciences and Engineering Research Council of Canada (NSERC); Ocean Spray; Ontario Ministry of Agriculture, Food and Rural Affairs (OMAF); Ontario Pork; The University of Western Ontario; Urex Biotech Inc.; and Wyeth Ayerst.

Urex Biotech Inc

Dr. Gregor Reid and fellow CRDCP scientist and urologist Dr. Andrew Bruce have been studying Lactobacillus for more than 22 years. They have isolated and patented two strains of bacteria, L. fermentum RC-14 and L. rhamnosus GR-1 that have been extensively tested in 15 human clinical trails. Their result has shown that daily oral use of the probiotic restores Lactobacilli in the vagina and reduces yeast, E. coli and other harmful organisms by more than 50 per cent. Reid and Bruce formed a company, Urex Biotech Inc., in 1988 to control their intellectual property, and currently hold 35 patents on the strains which they licensed to Chr. Hansen in 2004.⁴¹

 University of Laval - Nutraceuticals and Functional Foods Institute (INAF) (www.inaf.ulaval.ca )

INAF applies scientific knowledge with the aim of developing nutraceuticals and functional foods that improve human health through interdisciplinary research, education, technology transfer and communication. INAF proposes an innovative and integrated research approach, which includes the screening of bioactive molecules, the development of innovative and safe functional foods, and the validation of health benefits through clinical trials and economic perspectives.

More than 60 scientists and over 200 students are affiliated with INAF, specializing in the identification of promising bioactive molecules from a variety of natural sources including animals, plants, dairy and marine products, and ferments. Molecules of particular interest include antioxidants, phytoestrogens, conjugated linoleic acids, milk-derived peptides and probiotics. INAF has been very active in carrying out clinical trials for measuring the beneficial effects of functional foods and nutraceuticals on health - particularly in the areas of cardiovascular diseases, diabetes, obesity, immune system, cancer and women's health. INAF has gathered a large network of world-renowned scientists in nutraceuticals and functional foods from universities, colleges, hospitals and government research centres. INAF has a very strong focus on probiotic research in all areas of human and animal health.

McGill University

Affiliated with the Biomedical Technology and Cell Therapy Research Laboratory of the Department of Biomedical Engineering has eight scientists focused on probiotic research.

Agriculture and Agri-Food Canada

the leading AAFC research facility devoted to the study of probiotic for functional food, NHP, animal health and animal food use. The Food and Research Development Center located in St. Hyacinthe QC has five scientists devoted to probiotics.

Categories of Researchers

Of significance, none of the small number of those interviewed identified themselves as either NHP or nutraceutical researchers. Of those affiliated with academic faculties outside of medicine, many were working in close collaboration with the medical community. Many are biomedical researchers are physicians themselves (as per information derived from website analysis).

Some categorized themselves as food and/or nutritional scientists and only three indicated that their research included NHPs or nutraceuticals. In this group, food ingredient applications for their probiotic products are important and their research includes both a focus on capsule delivery system as well as the food delivery system. The latter involves ensuring that probiotics can be incorporated into foods and will remain bioavailable in food matrices. These researchers tended to be affiliated with Food Science and Nutrition departments in Universities (rather than departments in Medical Faculties or University teaching Hospitals) or with Agriculture Canada.

The NHPRP and CIHR Partnership Programs

None of the few researchers that were interviewed were aware of the NHPRP and the partnership program with CIHR. All of those surveyed have or are planning to apply to CIHR. The scientists surveyed for the most part lacked knowledge of the NHPD, the NHP Regulations and the NHPRP.

General Observations

Many of the general comments made by those surveyed for this project, especially under the topic of funding, are consistent with comments made at previous consultations and in past interviews with NHP and nutrition researchers.

A. The following section highlights comments made regarding the amount of funding available for probiotic and NHP research in Canada :

• This is a new area. There is a strong need for basic research - the fundamental principles are still very immature - microbiology and the understanding of cellular mechanisms is needed.
• More funding is required because probiotics are becoming well known and are quickly evolving in the market.
• Many researchers and funding agencies ask probiotic research should be included under NSERC, health, food, human disease? It falls in several places. The whole area of nutrition needs its own unique fund or a place for it.
• Universities are pressuring their researchers to bring in money. "You would be amazed at the number of meetings where the first discussion is how long will it take to get to the research to the market in order to bring in money. There is a preoccupation with this - universities looking for sources of money".
• Specific funding programs should be available for this research as probiotics fall under many of the various funding agencies.
• It has been very difficult to get some of the conventional health agencies to fund research in the area of nutrition as this falls outside the drug paradigm of disease treatment.
• NHP research including on probiotics is not seen as either food or drug related.
• To promote good research in this area, a pool of funds specifically targeted at probiotics should be established.
• It has been very difficult to receive funding for nutrition and probiotic research and almost impossible to secure money for clinical trials.
• "My Dairy Farmer funding was critical for me to generate data required for submission to granting agencies such as CIHR". This data is also required to leverage industry dollars.

B. The following section highlights comments made regarding the roles of the NHPD and CIHR in research funding in Canada :

Note that the researchers surveyed commented specifically on the CIHR, rather than other agencies such as NSERC, as it is the agency most associated with NHP research, the NHPD and NHPRP. The NHPRP and CIHR partnership was also discussed in this project. In addition, most researchers surveyed have in the past, or are planning to, apply to CIHR for clinical health related projects.

• Some concerns raised regarding the funding of probiotic and NHP and nutrition research within CIHR:
  • Need to strengthen the NHP knowledge base and awareness within the CIHR review committees.
  • Peer review process needs to be improved - there is a current bias in CIHR toward molecular and biomedical research, drug discovery and testing.
  • Competition for funding within CIHR is growing but there appears to be greater industry support for research with matching cash, as well as in-kind contributions.
  • Probiotic researchers are competing with traditional biomedical research and are being evaluated by reviewers who do not understand the area.
  • Several institutes in which probiotics are applicable are very drug oriented and biased towards molecular biology, cellular testing etc in their funding approach.

Key Themes and Suggested Next Steps

The following are identified as priority areas in the probiotic area by the NHP Directorate (NHPD) and the NHP Research program (NHPRP). It must be emphasized that these issues are the result of a very limited sampling of the probiotic research community and are meant to serve as a starting point for further consultations.

1. The need for further consultation and dialogue

An interesting finding of this project was that many of those involved in probiotic research specifically in the NHP area (i.e. not food or animal health) are medical doctors and clinicians. This appears to be unique in research involving bioactives commonly thought of as 'nutraceuticals' - that is ingredients from plants or animals with medicinal properties.

Of those affiliated with academic faculties outside of medicine, many are working in close collaboration with a medical professional, who is usually a gastroenterologist. Also, many are biomedical researchers or are physicians themselves. In this project, there was a challenge in communicating with the probiotic community focused in the medical field, and obtaining good information, as there was a general lack of response to interview requests. It can be noted as well that, from the information gathered in this project, it is difficult to determine what, if anything, the NHPD and the NHPRP can offer the medical doctor or physician involved in probiotic research. Thus further attempts at dialogue between the probiotic research community and the NHPD are required. The involvement of key researchers affiliated with the prominent probiotic research centres and clusters is also encouraged in any follow-up activities.

2. Greater interactions between probiotic researchers and the medical community

As noted, the diverse nature of the probiotic research community became apparent in this project. Research streams appear to be focused on activities which have a more agricultural base versus those which have greater biomedical and clinical application. The need to build partnerships and better coordinate research between these two areas will be important in the future in order to further build Canadian research capacity in probiotics. Mechanisms should be established to provide more opportunities for interactions between the two research communities as well as with scientists involved in other areas of NHPs in order to encourage synergies of common activities to avoid duplication.

A joint conference possibly hosted by the NHP Research Society and the AFMNet with the focus being aligning these two groups and providing the venue for networking and scientific exchanges is one suggestion. Such a conference would be similar to the two highly successful events hosted by the NHP Research Society, but more broadly based. Another suggestion would be to host a series of regional workshops.

3. Need for NHPRP information sessions

There appears to be a very significant lack of awareness among probiotic scientists and the medical community involved in probiotic research regarding the NHPD, the NHP Regulations and the NHPRP, including the partnership program with the Canadian Institutes of Health Research (CIHR). It is recommended that any consultations that the NHPD may undertake with the probiotic research community include an overview of the NHPD, the NHP Regulations and the research priorities of the NHPRP. In addition, information should be provided regarding how the partnership program with CIHR operates. Although it is recognized that this partnership program only began this year, it would be of value for the NHPD to provide informational workshops to the probiotic and NHP research community.

4. Mechanisms to support funding of probiotic research

Support for research in the application of probiotics and NHPs as alternatives to conventional health care was identified as a priority with an emphasis on the need for specific funding mechanisms. Funding directed to probiotic research is a relatively new area. Researchers are now seeking funds from 'conventional' sources such as the CIHR, the National Sciences and Engineering Research Council (NSERC), industry associations and increasingly from the industry. Most importantly, it was noted that the involvement of the medical community makes it more difficult for 'conventional NHP researchers' (i.e. those whose affiliation is not strictly with a medical faculty or who have not been involved in research related to pharmaceuticals, for example) to secure when the competition includes physicians.

There has been a reduction in direct funding and 100% grant programs over the past decade, and an increas e in the number of partnership programs with higher funding success rates (examples include industry associations and provincial funding) compared to investigator-initiated grants (i.e. through agencies such as CIHR). This concern was especially noted among those researchers with stronger ties to the agriculture or nutrition areas (i.e. as opposed to medicine) as well as those who are not funded to any significant degree by industry - several of whom were the same people.

Encouraging the continued funding support for probiotic research through Industry associations such as the Dairy Farmers and provincial agriculture and health departments is important as often this funding is for smaller scale research that is conducted as 'proof of concept' to accumulate the necessary data for submission to granting agencies such as CIHR. This data is often also required to leverage industry dollars for larger scale research. Additional funding from such sources could be encouraged through matching programs whereby the industry association and the government agency (federal and/or provincial) could each provide 50:50 funding.

In addition, industry research initiatives should be encouraged. A potential model is Agriculture and Agri-Food Canada (AAFC)'s Matching Investment Initiative Program (described in Appendix D of this report) where industry and AAFC match funding for AAFC directed research projects conducted on behalf of the industry. Perhaps this type of model could be explored as a way to establish partnership funding mechanisms from industry, association(s), provincial and federal sources overall for university health related research in NHPs.

Conclusion

This discussion paper identified an extensive and sophisticated scientific community actively involved in probiotic research in Canada . Probiotic research is being conducted to various extents across the country with Alberta having more focus on dairy based probiotics (mostly for animal health and foods) and the Eastern regions of the country conducting a significant amount of research in all aspects of probiotics for NHPs, food and animal health. In addition, four very strong research hubs exist in Eastern Canada (Canadian Research and Development Centre For Probiotics, McGill University , Institute for Functional Foods and Nutraceuticals (INAF), and Agriculture and Agri-Food Canada, St. Hyacinthe ) . Research activities are very comprehensive with many areas of health and disease conditions being studied at both the basic and applied levels.

Four broad topics and issues related to conducting probiotic research in Canada and with significance to the NHPD, the NHP Regulations and the NHPRP were identified as areas that could be explored further through consultations with the probiotic research community. Involvement of 'non-traditional' key funders identified in this paper - industry associations and provincial agriculture and health departments, is essential to ensure that such funding is maintained, and if possible increased, that dialogue continues and ties between all stakeholders are strengthened further. It is recommended that these funders are invited to any future consultations to explore ways to further support funding in this area. The involvement of key researchers affiliated with the prominent probiotic research centres and clusters is also encouraged in any follow-up activities.