Probiotics, Political Reform, and Creative Design

Probiotics, Political Reform, and Creative Design: Using Badges to Facilitate Innovation.

by Greg Emmerich  December 17, 2011.  UW Madison MS Biotechnology Program: Regulation and Ethics Final.

Abstract

Understanding of the biological world has increased dramatically since Robert Koch first formulated his postulates connecting microbes to diseases some 120 years ago. Since then, scientists have uncovered much about the physiology, genetics, and ecological role of many bacteria. Scientists have primarily been focused on disease associated with microorganisms, and are just beginning to explore the estimated plethora of activity microbes play in establishing human health through the Human Microbiome Project (HMP). There is still much to be learned, but already it is clear that some bacterial strains have varying levels of benefit for humans. Numerous health-conscious consumers have been looking towards probiotics to help promote good health and possibly stave off illness, and industry is eager to make bold claims to capture that market. Protecting these consumers’ from unsafe products and from being swindled by false claims is the role of the Food and Drug Administration (FDA). Currently there is much debate over the regulation of probiotics and prebiotics. Finding an appropriate solution to the problem requires a creative approach. To aid consumers in evaluating health claims on products and to incentivize more research to be conducted, a simple solution of improving the labeling on those products is suggested. Creating a new regulatory category for probiotics and prebiotics may be appropriate if measures of efficacy can be demonstrated more convincingly.

Content

Scientific Background

Research Difficulties

Current Probiotic Regulation and Difficulties

New Regulatory Category Considerations

Figure 1 – Health Claims Rating System for Labeling

Appendix – Survey Questions and Results

Bibliography

Scientific Background

Connections between humans and bacteria have slowly been teased out through the years via scientific research. Unbeknownst to early humans, microbes played a key role in the formation of civilization due to their ability to ferment grains into alcohol which motivated hunter gatherers to settle down to plant grains, and consequently develop societies (Mirsky, 2007). While the health benefits of beer may be somewhat questionable, numerous recent studies have shown just how much of an impact bacteria can have on humans.

Not only is the question always how much, but sometimes it is how many. The truth of the matter is that bacteria are everywhere and it is not possible to live without them. Human cells are outnumbered 10 to 1 by resident bacteria cells, mostly through the gastrointestinal tract. The amount of information encoded in the genomes of all those bacteria far outweighs that of the human genome (Shanahan, 2002). It goes without saying that this should prove pertinent for humans to understand their own microbiota, but to what extent this information is useful is only beginning to be explored. The concept of utilizing bacteria proactively to improve health is not a novel idea, and in fact goes back over 100 years to Eli Metchnikoff, a Russian biologist, who suggested replacing harmful bacteria in the human flora with useful ones. He hypothesized that consuming lactic acid producing bacteria would “enhance longevity” (Metchnikoff, 1908).

The definition of probiotics given by the FAO/WHO is “live microorganisms which when administered in adequate amounts confer a health benefit on the host” and will be used in this paper. There is great promise of probiotics for use in medical treatment but limited scientific knowledge exists upon the efficacy of such treatments. The line begins to blur when it comes to understanding what is real and what is fiction. This confusion is propagated by an industry eager to capitalize upon an market estimated to be in the billions of dollars per year (Stanton et al., 2001). Thankfully, with the spurred interest, more research is being funded and mechanisms behind beneficial probiotic effects are being discovered.

Key benefits of bacteria are the many protective, structural, and metabolic effects they establish for humans. Commensal bacterial are crucial for the development of the innate and acquired immune systems (O’Hara and Shanahan, 2006). Studies of animals kept germ-free show they have impaired mucosal immune systems and reduced digestive enzyme activity (Shanahan, 2002). These consequences are not permanent, and in fact once bacteria recolonize the animals intestines, the mucosal immune system is restored to its proper level (Umesaki et al., 1995). A diverse microbiota provides a barrier to infection and furthermore individual strains compete against other bacteria of the same genus or family (Freter et al., 1983; Wells et al., 1988). Competition for nutrients likely drives much of this, and some have proposed that bacteriocins are produced by certain bacteria to combat against other strains (Walker and Buckley, 2006). Improved acquired immunity through probiotics has not conclusively been proven.

The microbial flora varies from person to person. This is influenced by lifestyle, diet, and age to an extent (Hopkins et al., 2001). Predominantly it is the particular genotype of the individual person that effects their microbial diversity (Zoetendal et al., 2001). Colonization of infants occurs as early as birth, and is further supported by any contact with microorganisms through other people or animals, or through consuming any microbial-laden food (Walker and Buckley, 2006). Within two years the microbiota of infants becomes relatively stable (Midtvedt and Midtvedt, 1992). The overall stability of human adult microbiota is fairly high, although specific bacterial strains may experience high turnover, supporting the conclusion that there is much competition among bacteria to colonize the human gut. The mouth and colon appear to be more stable than the rest of the intestine (McCartney et al., 1996).

One issue with a stable microbial community is that it can be difficult to change its composition and retain the new composition, which is one of the desired effects for probiotics. Microbial populations return to normal after antibiotic treatment (De La Cochetiere et al., 2005), and those populations may be more resistant to changes after they have adapted to the stressor (Rachmilewitz et al., 2002). There also is an indication that prebiotics may create more significant changes upon the microbial populations than probiotics by creating a nutritional environment condusive to certain bacterial strains.

Research Difficulties

While many scientists pride themselves on being able to solve challenging problems, certain areas of study are inherently more difficult than others. Such is the case with probiotic research, for a number of substantial reasons. First among them would be the arduous task of conducting meaningful studies where the effects from probiotic administration are easily and clearly measurable. Currently a large deterrent to executing such studies is the heavy burden of proof and steep application fees required similar to that for drugs. Proving efficacy and creating a good framework for research to be conducted under would generate the greatest potential health benefit for the general public.

Probiotics present a unique challenge to researchers. By virtue they are living organisms and thus they are dynamic and have many variables that sometimes might not be obvious. Bacteria respond to wide array of environmental stimuli which can significantly affect how well they perform at a given task. Changes in the activity level or metabolism of human subjects and changes in diet both would affect potential responses of the bacterium (Zoetendal et al., 2001). Interactions between the probiotic strain in question and other microbiota are crucial to understand, as well as with the host immune system. Genetic regulation is an incredibly complicated field where new discoveries can greatly reshape our understanding of microbial function. For example, prions, a recent discovery themselves, more recently were found to be capable of altering natural protein folding in E. coli cells (Garrity et al., 2010). This demonstrates how easily our firm understandings of science can be undermined by new results and raises the question as to how many significant factors are currently at play to which scientists are in the dark about.

A difficulty for all microbiology research is simply being able to study the subject of interest. At least half of the resident bacteria in the human flora can not be cultured by standard techniques and identification of individual species is difficult (Shanahan, 2002). Filling this void of knowledge is a goal of the Human Microbiome Project (HMP). The metabolism of some bacteria are heavily interdependent upon the metabolism of other bacteria, yet the crux of microbiology research is characterization through isolation. Thus the HMP has a very lofty goal which might require new methods of analysis, and certainly will require more time. Once the human gut flora is better characterized, it is hoped that the importance of different levels of particular genera, species, or strains of bacteria will be understood (Sanders et al., 2005). Being able to understand the interactions among microbes might prove very useful for being able to determine the efficacy of probiotic treatments in clinical trials, especially for probiotic strains claiming to be able to out-compete potential pathogens.

There are other barriers to making it to clinical trials. First, an appropriate organism must be selected, then in vitro testing and in vivo animal models must show safety and efficacy. The traits suitable for a particular bacterial strain to be tested as a potential probiotic depends on the target site of probiotic use (e.g. oral, vaginal, or intestinal application), as well as how the probiotic is being delivered (Rauch and Lynch, 2011). Not only must the selected bacterium be non pathogenic but it must also be unlikely to infect immunocompromised individuals and not be able to perform horizontal gene transfer of antibiotic resistance to pathogens (Walker and Buckley, 2006). The difficulty of replicating epithelial adherence in vitro makes these studies less useful since adherence is critical for many commensal microorganisms (Walker and Buckley, 2006). The natural flora differs between animals and humans which muddles comparisons between the two with in vivo studies. These studies are useful for understanding key mechanisms underlying probiotic effects like producing desired metabolites, but add another hurdle to overcome.

What might be the most significant and relevant problem with probiotic research is in determining relevant endpoints and biomarkers with which to measure an effect. Clinical trial endpoints are the proof that the particular compound in question does what the manufacturer claims it does and are of the utmost importance (Chin, 2004). The relevancy of those endpoints to a meaningful effect for the patient is crucial, and has presented a great difficulty for probiotic researchers. Common probiotic endpoints are: reduced incidence, duration, or severity of common infections; reduced symptoms for irritable bowel syndrome; improved immune function; improved digestive function; and balancing intestinal microbiota. Of these, only digestive function and intestinal microbiota have validated biomarkers—a normalized intestinal transit and decreasing potentially pathogenic intestinal microorganisms, respectfully (Sanders, 2011). More research is necessary to elucidate useful biomarkers and prove efficacy.

The issue is further complicated by the fact that placebo effects in probiotic clinical trials can be quite significant and difficult to properly address (Walker and Buckley, 2006). Creating placebo products can be challenging with probiotics since the control foods may contribute to a physiological effect even without the active bacterial culture. The placebo effect matters more to probiotics because the difference between the desired effect and baseline is generally much less significant then when comparing a drug to its control substance (Sanders et al., 2011). Being able to create a placebo-controlled and blinded study for probiotics is sometimes mutually exclusive. Control groups may not realistically be able to have zero intake of a food type (Sanders et al., 2011)

Difficulties measuring an effect from probiotics goes beyond placebo concerns and includes the attitudes and lifestyles of their consumers. Maintaining proper health is very much a multifaceted practice. People who are more likely to consume probiotics could be promoting other aspects of a healthy lifestyle which could contribute to any noted changes in test subjects’ health. These kind of consumers are more likely to be concerned with nutrition, fitness, stress, and their environment (Kraft and Goodwell, 1993). The extra “noise” from these factors makes drawing conclusions from clinical studies more challenging.

Selecting a proper group for human study can be a balancing act. On the one hand, a broad selection from the general population is desired in order to make representative conclusions, but on the other hand, a homogeneous selection can reduce “noise” derived from any of the numerous complicating factors described above (Sanders et al., 2011). For obvious ethical reasons any study subjects must give their full consent, and it may be the case that more health-conscious consumers are more often volunteering for probiotics studies. Difficult problems rarely have simple solutions, and in the case of probiotics, a broad sampling of host microbiota is likely needed to gain a better picture of probiotic efficacy as well as an appropriately powered study size.

As if the scientific difficulties were not enough for probiotic research, there are numerous regulatory concerns that deter industry and academia from conducting research in the first place. Studying healthy people can increase the time requirements of clinical trials and the costs from this and monitoring so many variables can be prohibitively high. Regulatory issues will be explored more in the next section.

Current Probiotic Regulation and Difficulties

As science and technology develop, new and unanticipated challenges face the FDA in terms of maintaining safety and proving efficacy. Regulations are created to broadly cover different products in response to the uncertainty of future needs. Probiotics present a unique situation because of their claims to prevent and treat disease similar to that for drugs, yet they are naturally found in the human flora and are being delivered through conventional foods like yogurt. In order to analyze the merits of a creating unique regulatory category over existing ones, the current state of probiotics regulation under the FDA will be discussed. Since different countries have their own regulations about probiotics, an international perspective will be emphasized considering lessons from the European Union and Canada. These considerations as well as public perception could influence researchers to pursue probiotic formulations or avoid them altogether.

How probiotics are regulated depends on their intended use. This could mean probiotics could be regulated as food or food ingredients, as medical foods, as dietary supplements, or as a drug or biological product. Largely, probiotics have been under the conventional foods or biological product categories. The reason behind regulations and the purpose of the FDA is to protect the public health (FDA, 2011). Biological products containing a whole, live microorganism are regulated under section 351 of the Public Health Service Act, 42 U.S.C. 262. A biological product is defined as:

… a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.” (42§262)

where a ‘virus’ can include bacteria and other microorganisms. Requirements are that the “biologic product that is the subject of the application is safe, pure, and potent”, the manufacturing facility meets these standards, and an inspection of the facility is conducted (42 USC 262). A Biologics License Application (BLA) is submitted through the Center for Biologics Evaluation and Research (CBER) to gain approval to market a Live Biotherapeutic Product (LBP). This is done when the LBP is intended for the use of preventing or treating a disease, and requires clinical trial results from an Investigational New Drug (IND) Application (21 CFR part 312). The requirements and fees for INDs are steep, and include (i) a description of the composition, manufacturing process, and control testing of the drug substance and drug product, (ii) pharmacological and toxicological studies of the drug in vitro or in animal models to support the proposed clinical investigation, (iii) previous human experience, if any, (iv) proposed clinical study protocol, and (v) any other information deemed relevant for review. Filing costs for applications requiring clinical data are over $1.8 million, or over $0.9 million when not requiring clinical data (Federal Register 76:147, 2011).

The proof required for substantiating a health claim to the FDA has become less strict in recent years but is still significant. Evidence could consist of experience, long standing traditional use, animal studies, case studies, in vitro experiments, and clinical trials (FDA, 1999). The FDA authorizes health claims to be used on conventional foods if they

determine based on the totality of the publicly available evidence (including evidence from well-designed studies conducted in a manner which is consistent with generally recognized scientific procedures and principles) that there is significant scientific agreement among experts qualified by scientific training and experience to evaluate such claims, that the claim is supported by such evidence.” (21 CFR 101.14(c))

This was the principle of significant scientific agreement (SSA). This was somewhat dismantled after the court case Pearson v Shalala ruled in favor of Pearson, a dietary supplement manufacturer. From this decision, the “court held that the First Amendment does not permit FDA to reject health claims that the agency determines to be potentially misleading unless the agency also reasonably determines that a disclaimer would not eliminate the potential deception.” This spurred the creation of qualified health claims as a way to evaluate health claims that fall in between emerging evidence and SSA (Emord, 2000). In 2002 the FDA extended their qualified health claims approach to conventional foods in addition to dietary supplements (67 Fed. Reg. 78002). The FDA still requires pre-approval for these claims, however, and a disclaimer is required stating “This product is not intended to diagnose, treat, cure, or prevent any disease.” The FDA will not change its approach for evaluating the scientific evidence in petitions, but if the evidence doesn’t meet SSA then it will be evaluated if the evidence supports a qualified health claim. The highest level of confidence for a substance/disease relationship is still SSA and is awarded when scientific consensus is unlikely to be upturned by new and evolving research (FDA, 2009). Being able to describe the mechanism behind the effect is regarded very highly but is not required (Sanders et al., 2005).

Health claim approval in the US follows a list of criteria set by the FDA. In brief, the FDA looks at the strength of the 1) quantity, 2) consistency and 3) relevance of any supporting scientific evidence. In evaluating the totality of such evidence, the FDA looks at the study outcomes, study type and persuasiveness, number of the various types of studies and sample sizes, relevance of the evidence to the target subgroup, replication of the results by others, and the overall consistency. The outcome of the study needs to show statistical significance of the linear relationship between the substance and disease as well as of the risk between subjects at the various levels of intake. Interventional studies are highly valued and viewed stronger than even conflicting observational evidence (FDA, 2009). The persuasiveness of the study methodology to the FDA, ranked from high to low, is:

  1. Randomized controlled clinical study

  2. Longitudinal study

  3. Case-control study

  4. Cross-sectional study

  5. Uncontrolled case series or cohort study

  6. Time-series study

  7. Cross-population study

  8. Descriptive epidemiology

  9. Case report (FDA, 2003)

Even though this guidance from 2003 has been replaced, the basic principles have not changed and this persuasiveness scale still holds true. Relevancy includes having a representative sample and that the benefit from the substance significantly exceeds normal intakes. Consistency with other studies increases the confidence that the subject in question actually produces the measured effect, and conflicting results lessen this. (FDA, 2009). While animal studies are helpful, it should be noted that human data is required to substantiate health claims.

The non-binding recommendations regarding IND submissions for early clinical trials with Live Biotherapeutic Products are currently in the process of being modified by the FDA, and will represent their opinion on LBPs once finished (US DHHS, 2010). The only exception from IND submission while still claiming health benefits is if the product is “generally recognized as safe” (GRAS) or “generally recognized as effective” (GRAE), which require a similar amassing of scientific support behind any health claims. Attaining ‘generally recognized’ status is desirable for companies who are looking to relieve a great deal of burden upon themselves and market a product where many others have proven the safety of that product. However, because of the largely exploratory nature of research surrounding probiotics and the incentives to patent new genetically engineered probiotic strain discoveries, GRAS and GRAE are not as useful for probiotic researchers. That is, once a patentable discovery has been made and granted by a region’s patent office, the company or assignee gains a legitimized competitive advantage to prohibit others from selling that same probiotic formulation. Patent considerations are incredibly numerous and will not be fully addressed in this paper.

The creation of qualified health claims further led the FDA to try improving consumer awareness of them. They assembled a ‘Task Force’ on ‘Consumer Health Information for Better Nutrition’ oddly reminiscent of the Warner Brothers ‘Justice League’ series, but instead of fighting the forces of evil, the Task Force’s aim was to “provide more and better information to consumers about the health and nutritional benefits of their products,” whereby, “Armed with more scientifically based information about the likely health benefits of the foods and dietary supplements they purchase, consumers can make a tangible difference in their own long-term health by lowering their risk of numerous chronic diseases.” (Consumer Health Information, 2003). Even with as much bravado as the Task Force’s self description has, in reality it is much more challenging to effectively educate consumers. In a recent small survey, 45.2% of respondents said they never or only sometimes look at a food product’s nutrition information, compounded with 53.9% of respondents stating they have no clue or are only somewhat familiar with probiotics (see Appendix 1). An effective system for easily and clearly differentiating health claims on product labeling is needed, as is further discussed in the next section ‘Proposed New Regulatory Category.’

In short, the difference between structure/function claims and disease claims is fairly significant in the eye of the FDA, and there is good reason for this. Thorough research which has proven the relationship between a substance and a disease deserves to be marketed as such and thus attract more consumers with the related health condition to that product. Research that is not adequate does not deserve the same rights, and consumers shouldn’t be allowed to be so swindled by “snake oil” or other pseudoscience. This still by and large happens right in front of the FDA, however. The Dietary Supplement Health and Education Act of 1994 (DSHEA) basically allows unsupported structure and function claims as long as they do not make direct disease claims. These are claims that a product can support, boost, enhance, or improve some structure or function of the body. The difference between structure/function claims and health claims in the eye of the consumer is not so clear, as highlighted by the success of many companies based around pseudoscience such as the Power Balance. Regulatory authorities hopefully recognize more such quackery, and in the case of Power Balance they were forced by the Australian Competition and Consumer Commission to say “there was no credible scientific evidence to support their claims.” Industry may be very eager in the case of probiotics to make bold claims before the science supports them in order to attract customers, and this should be regulated against. Every false claim about probiotics that enters the marketplace only damages the credibility of probiotics for consumers, creating considerable barriers for future manufacturers with scientific proof to have to overcome.

Health benefit claims of probiotics and prebiotics are viewed differently by consumers, healthcare professionals, regulators, legislators, and scientists (Sanders et al., 2011). These different viewpoints extend beyond the US and are prevalent through varying probiotic regulations in other countries. The FDA, EuropeanFood Safety Authority (EFSA), and Canadian Natural Health Products Directorate (NHPD) have very different standards as to when a health claim is sufficiently substantiated by the manufacturer (Sanders et al., 2011). Europe has much stricter regulations in place around all health claims. The EFSA subscribes to the “strong scientific basis on the highest level” to back up any claims, and any failing to do so are rejected. Risk reduction and structure/function claims are allowed but must meet the same rigors of evaluation. The criteria for scientific substantiation of claims is as follows:

  1. The food or food component to which the claimed effect is attributed should be characterised.
  2. Substantiation of a claim should be based on human data, primarily from intervention studies the design of which should include the following considerations:
    1. Study groups that are representative of the target group.
    2. Appropriate controls.
    3. An adequate duration of exposure and follow up to demonstrate the intended effect.
    4. Characterisation of the study groups’ background diet and other relevant aspects of lifestyle.
    5. An amount of the food or food component consistent with its intended pattern of consumption.
    6. The influence of the food matrix and dietary context on the functional effect of the component.
    7. Monitoring of subjects’ compliance concerning intake of food or food component under test.
    8. The statistical power to test the hypothesis.
  3. When the true endpoint of a claimed benefit cannot be measured directly, studies should use markers.
  4. Markers should be:
    1. biologically valid in that they have a known relationship to the final outcome and their variability within the target population is known;
    2. methodologically valid with respect to their analytical characteristics.
  5. Within a study the target variable should change in a statistically significant way and the change should be biologically meaningful for the target group consistent with the claim to be supported.
  6. A claim should be scientifically substantiated by taking into account the totality of the available data and by weighing of the evidence. (Aggett et al., 2005)

Canada has outlined some rather specific criteria for evaluating structure/function claims, risk reduction claims, and disease treatment claims. The Natural Health Products Directorate does not recommend general effect claims, such as “improves gut health,” but rather specific effect claims like “improves nutrient absorption.” They require strain specific evidence for probiotics since not all strains of a species have probiotic activity (Food Directorate, 2009). In Canada, probiotics are currently regulated as food ingredients or as natural health products (NHPs) similar to dietary supplements. They do not have specific regulations for probiotics in foods. The NHPD assessment for credibility of evidence is as follows:

  1. Is the reference generally available?

  2. Is it widely recognized and used?

  3. Are the authors knowledgeable in their field?

  4. Do the authors cite their sources?

  5. Has the reference been peer reviewed?

  6. Is it used in other jurisdictions?

  7. Does it present balanced data?

  8. Is it based on the totality of existing evidence?

  9. Has it been commercially published?

  10. Is it the most current information or edition available? (NHPD Guidance Document, Ch. 5.1, 2006)

The ranking of the strength of evidence roughly follows the same as under the FDA. The quality of evidence within each type considers the following factors:

  • Were the objectives of the study defined?

  • Were the methods and outcome measures or endpoints clearly defined?
  • Was there a clear description of the inclusion and exclusion criteria?
  • Were the methods of statistical analysis adequate and well-described?
  • Was there at least one control (comparison) group?
  • Was the study randomized?
  • Was the study double-blinded?
  • Was any risk information described, such as adverse reactions or reasons for participant dropout?
  • Was the medicinal ingredient in the study adequately identified (e.g. proper name) and characterized (e.g. extraction method, chromatographic fingerprint)?
  • Were potential sources of bias adequately addressed?
  • Was the study published in a well-recognized, reputable source?
  • Was the study peer-reviewed?
  • Did the authors cite (reference) their sources? (NHPD Guidance Document, Ch. 5.3, 2006)

In looking at the totality of evidence, the NHPD considers the amount adequate when it 1) specifically supports the claim and all remaining recommended conditions of use, 2) is from relevant levels, 3) reflects the concept of self-care, 4) reflects the totality of evidence, 5) is from reputable and well-recognized sources, 6) is mostly of high quality and 7) supports the safety of the product when used according to the recommended conditions of use (NHPD Guidance Document, Ch. 5.4.1, 2006). While some of these criteria may seem obvious, they provide a much stronger basis for probiotic researchers than US guidelines and provide some inspiration when assessing new US probiotic regulations.

There is a clear need to regulate probiotics, but doing so presents difficulties. Not all probiotics are created equal. Probiotics have varying levels of risk and potential benefit associated with them, yet currently in the US all probiotics making health claims are regulated the same by CBER. The susceptibility of the patient to opportunistic infection, dose and duration of probiotic consumption, and the mode of administration all add complexity to safety concerns (Sanders et al., 2010). General consensus agrees that good manufacturing standards need to be put in place and that accurate strain characterization is established (Sanders et al., 2011). Evidence shows that some labels falsely advertise the organisms present in their products (Huff, 2004; Elliot and Teversham, 2003). Putting strong standards in place would assure customers of a probiotic product’s quality and that it can be expected to deliver on the claims it makes.

Out of necessity for clear-cut enforceability of regulations, there are strict divisions between health and disease (Sanders et al., 2011). This is of concern for probiotics and prebiotics because their beneficial effects tend to fall somewhere in the middle. A growing body of evidence from the scientific community suggests that some foods may decrease the risk of certain diseases, like for example the flavonoids found in cranberries reducing the risk of Atherosclerosis (Reed, 2002). In order to make such definitive health claims, however, more rigorous clinical trials are required. Considering that the average costs of moving through clinical trials is estimated around $900 million and only about 1 in 5 products actually make it through to approval, it is understandable why researchers are so hesitant to pursue that route (DiMasi et al., 2003; DiMasi et al., 2010). Herein lies one of the arguments for creating a new regulatory category for probiotics that would allow an abbreviated approval process, thus incentivizing probiotic research and ultimately having the greatest benefit for the public. The nature of the beast is cyclical, however, with both sides relying on the other to move forward.

New Regulatory Category Considerations

In considering the merits for creating a new regulatory category for probiotics, many factors need to be scrutinized. The nature of politics in the US is crucial to understand before proposing any new legislation. The poster child for demonstrating the importance of knowing how the public will react to new science is stem cells, although ethical issues related to probiotics are not nearly so prevalent. A proactive approach to educating the public about probiotics is recommended. This could be done through improving labeling to assist consumers in differentiating between levels of scientific support for health claims. Creating a new regulatory category for probiotics may result in an environment favorable to probiotic research, but in order to justify such an act and pass legislation through congress, measures of efficacy need to be demonstrated more convincingly.

Politics have become increasingly polarized as of late. It can be incredibly difficult to find compromise and bipartisanship in the current political climate, making it more difficult to pass any sort of legislation. Considering the vastly different opinions individuals may have about any issue, in order to make any sort of change, compromise is necessary more often than not. President Barack Obama himself called on Republicans and Democrats to “put aside their differences… After all, both parties share power. Both parties share responsibility for our progress” in his weekly address on August 6th, 2011. It very well may be that the source of difficulty in compromising is the nature of the democratic process itself. Politicians are incentivized to stay on a course of permanent campaigning in order to retain their own jobs through the next election cycle, which encourages attitudes and arguments that make compromise more challenging (Gutmann and Thompson, 2010). This perpetual state of campaigning also leads politicians to remain focused on financing their future efforts and appeal to parties who are willing to make larger donations to them, so long as politicians fight for what those parties have a vested interest in. The 2008 average cost for state legislator campaign was $65,000 and is only expected to go up, especially when two opposing candidates are fighting hard for a seat (Crumm, 2009).

A recent Supreme Court case, Citizens United v FEC, overturned previous rulings that corporations could not use general treasury funds to support or oppose political candidates (No. 08-205, January 21, 2010). Justice Stevens led the dissenting opinion and voiced the concern that the ruling “threatens to undermine the integrity of elected institutions across the Nation,” and concluded that,

“At bottom, the Court’s opinion is thus a rejection of the common sense of the American people, who have recognized a need to prevent corporations from undermining self government since the founding, and who have fought against the distinctive corrupting potential of corporate electioneering since the days of Theodore Roosevelt.”

Allowing unlimited spending on political campaigns without public disclosure likely would prove to give special interests and lobbyists even more power in Washington. This decision radically changes the political landscape in America. This is the battlefield that probiotics would be entering. The aforementioned suggestion that permanent campaigning makes it more challenging to pass legislation without large financial backing from corporations and wealthy individuals is supported by the Citizens United v FEC ruling. Furthermore, any politician strongly speaking out against the interests of large corporations is likely subject to a barrage of TV ads attacking them and hurting their chances for reelection. This works to effectively pacify politicians. This challenge doesn’t appear to be leaving anytime soon.

During his weekly address on August 6th, 2011, Obama spoke in favor of creating a business environment conducive to job creation. Specifically, “We have got to cut red tape that stops too many inventors and entrepreneurs from quickly turning new ideas into thriving businesses.” There is a lot of potential for probiotics to create new businesses and to improve the health of the public, but in order to realize this potential, an environment conducive to probiotic research must be created. This depends upon improving probiotic regulation. The potential for successfully doing so is uncertain. The Citizens United v FEC decision may actually help probiotics since large companies may lobby for an abbreviated approval process, even though the more credible reasons behind doing so should be enough. An important consideration is the public’s perception of probiotics. Again, some larger companies have already undertaken positive marketing campaigns, but a misunderstanding of probiotics could create some resistance in Washington.

Science in general tends to be misunderstood by the general public. Only about 28% of American adults are considered scientifically literate. This was defined as “the level of understanding of science and technology needed to function in a modern industrial society. This … does not imply an ideal level of understanding, but rather a minimal threshold level.” (Miller, 2007). For example, this level of understanding would be enough to understand about two thirds of the scientific concepts that might be found in the New York Times weekly science section or in an episode of the PBS program “NOVA.” This lack of knowledge about science could be self-propagating. In a recent study it was found that ignorance about a scientific or economic issue results in avoidance of learning about that issue, through dependence and trust of the government. In addition and rather disturbingly, the more urgent the issue, the more people wished to remain unaware (Shepherd and Kay, 2011).

The importance of scientific literacy is shown several ways. For one, a scientifically literate work force is required for a country where innovation is idealized. There is also an increasing amount of public policy controversies surrounding new scientific issues. This has been exemplified with stem cells, but thankfully probiotics do not have nearly the same amount of ethical issues. The products consumers are purchasing are becoming more complicated and require a better understanding of the scientific basis behind the product in order to make informed purchasing decisions. Not everyone may be interested or enjoy learning about science, but the fact of the matter is that science is affecting their lives more and more. The trend for scientific literacy is favorable, however, and has nearly tripled from 1988 to 2005 (Miller, 2007).

One way to create an environment where truly great science is not misunderstood and prohibited is to improve the accessibility of science and improve education. One very promising sign is the fading “ivory tower” syndrome. Citizen scientists have been on the rise, taking control of their own medical data such as genetic test results and analyzing scientific data for themselves. They also run experiments using the internet. Genetic Alliance, led by Sharon Terry, promotes citizen science and education around genetics (Marcus, 2011). While citizen scientists show great initiative by taking matters into their own hands, it is duly noted that they may not apply the same rigor in analyzing data or setting up studies. The internet has proven invaluable for creating access to information, but the problem arises that not all that information is accurate. To properly navigate through the overwhelming amount of sometimes contrary evidence, a skeptical and analytical attitude must be taken. This is perhaps the greatest benefit that science education can have upon the public, and in fact, Miller believes that the requirement for non science majors in college to take two semesters of science is one of the main reasons for improved scientific literacy (Miller, 2007). Thinking skeptically can be very liberating because it allows an unbiased approach to decision making. A mindset that is asking questions and addressing uncertainty can serve as a barrier against manipulation, fraud, and misinformation.

The curiosity that drives scientists is something that all children can relate to. Carl Sagan once said that they share a sense of wonder and awe at the natural world. This curiosity is important because “new ideas are not generated by deduction, but by an artistically creative imagination” as Max Plank, the founder of quantum theory, once said. It is these new ideas that drive innovation, and it is innovation that both sides of the party line can agree upon. There are many wonderful science outreach programs for children, and this hopefully will continue provided that education funding is not significantly reduced. Children are able to interact with science in ways that they never were before. Video games on basic scientific concepts can get children excited to learn about science and make education fun, as UW researcher Susan Millar has done with education on viruses. By rewarding children for learning, or creating positive reinforcement, the motivation for continuing to learn and succeed increases.

Educational outreach may be necessary for adults, too, since some still think of bacteria as “bugs” and may be adamantly opposed to probiotics. The misinformation may not be purely a generational gap. In a small survey conducted by the author, 31 respondents varying in age from 19-26, all friends and peers of the author, gave their responses to a series of questions pertaining to probiotics. Participation was completely voluntary and was advertised using Facebook. The author predicted that his peers who would receive notification of the survey would all be college educated or nearing completion and thus would be more informed than the general public about a current issue like probiotics. The level of probiotic literacy for the general public is unknown, however. The results were somewhat surprising, since 53.9% of respondents stated they have no clue or are only somewhat familiar with probiotics (see Appendix 1). From this study it is clear that this issue should be further probed, since the categories were completely arbitrary. The purpose was to get a general understanding of public perception of probiotics, however, which this study showed was favorable with a young audience since 65.4% of respondents said they would probably or absolutely consider buying a probiotic food product.

Even among people who have a good understanding of probiotics, the current regulatory system for probiotics is at minimum unclear and leaves many questions for consumers, researchers, and industry. Encouraging scientific research on probiotics is in the best interest for regulators to improve public health. Strong measures of safety and efficacy need to be enforced to protect consumers, but these are dependent on scientists devising new methods of testing as described in the ‘Research Difficulties’ section. The situation is a sort of catch-22. The most logical solution would be adapt the regulations as the science progresses, but political difficulties make this option far from ideal. An understanding of what scientists are currently capable of showing in terms of safety and efficacy is needed before proposing any legislation, and was shown in the ‘Research Difficulties’ section. From here, though, the future is uncertain. Often is the case for many important decisions the FDA has to make. They would hope to create regulation that will be flexible enough to fit future needs but is rigid enough to be clearly enforceable. How to do so with probiotics is not apparent from previous regulation. It is from here where new ideas are necessary. It is from here that deduction fails and like Plank said, “artistically creative imagination” steps in.

The core of the issue with probiotics regulation is aiding the consumers. Consumers are truly the ones driving the demand because they will be the ones buying the products and ultimately paying for the research, and should be the center of attention when proposing new regulation. The current state of ‘qualified health claims’ is beyond the expectations for most consumers to care to understand. There is a great desire to help healthcare consumers find, comprehend, and interpret health information before making informed decisions (Soergel et al., 2004). As plainly as possible, they want to see what benefit they will get from a probiotic food and feel comfortable trusting what they read on the label. Currently any label making a claim that does not have strong scientific agreement (SSA) must have a disclaimer that “This statement has not been evaluated by the Food & Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.” This does not give any indication about how supported the health claim is. As straightforward as the disclaimer may be, this is only shown on the back or side of labeling and many consumers (45.2% of survey respondents in Appendix 1) may only look at the nutrition information and other details very infrequently.

A solution needs to be simple and easy to understand as well as not constrict industry more than necessary. The public education system may provide an insightful lesson that is applicable to probiotics research. Many teachers have long spent wondering how best they can educate their students. Simply providing students with the correct information in text form is often not enough. Indeed, research indicates that pictures can be very helpful in improving students’ learning (Carney and Levin, 2002). Written and visual information work together to create meaning for the student. Use of multimedia in education has increased dramatically over the past 20 years and incorporates not only pictures but video into lecture material throughout universities. Fascination with pictures is not a recent trend, as illustrated by paintings on cave walls from the beginning of mankind. This all goes to support how useful pictures can be in helping to transfer complicated information. Furthermore, pictures and graphics can be aesthetically pleasing, and have been successfully used by marketers for many years in delivering information to their consumers. Disclaimers that companies are required to put on labels are not well designed and therefore companies may be more accepting of a graphical disclaimer than a text-based one.

Probiotics, dietary supplements, and conventional foods all could benefit consumers from including interpretational graphics onto product labels. Interpretational graphics are simply illustrations that help to clarify difficult-to-understand material and usually describe a cause and effect system. This benefit would be especially pertinent for consumers with low prior knowledge about probiotics or about the amount of scientific support certain foods may have in improving health, as drawn from a finding that unknowledgeable students benefited most from comprehensive, informative visual illustrations (Ollerenshaw et al., 1997). This would theoretically seem to be of great value for probiotics that need to convey difficult information about the effects of taking any such products. Creating meaningful and relevant graphics would be essential, as Ollerenshaw et al. describe.

There are many possible ideas for implementing interpretational graphics, but the one presented in this paper is thought to fulfill all such needs. The following figure is a suggestion for differentiating the levels of scientific support towards health claims on probiotic, dietary supplement, and conventional food labels.

Figure 1.

Figure 1. A graphical rating system for distinguishing between levels of scientific support for health claims on probiotics, dietary supplements, and conventional foods labels. The images are suggested to be placed immediately following each health claim in a superscript position.

The images are meant to convey ideas inherent in the illustration and not require any background knowledge to be able to ascertain which product has the most support behind its health claim. Testing was done on the same set of survey respondents that answered questions about reading nutrition information labels and on knowledge of probiotics. Figure 1 is a modified version of the “health claim badges” that respondents rated, where the images seen in Figure 1 as “Promising Scientific Support” were simply a star instead of two hash marks and a star (see Appendix 1). Respondents were asked to imagine they “were going to buy a food item because it had some claimed health benefit, knowing that certain foods have more of an effect on health than others.” They were then shown four theoretical food labels all generally claiming “This product is good for your health” with the difference being which of the four graphical images was next to the claim. After seeing this they were asked to rank the images in order of perceived health benefit. The expected result was that the star would rank the highest (alluding to a general’s status in the military or as popularized in various ‘Mario’ games by Nintendo), followed by the plus sign, then the double and single hash mark images. However, maybe due to the prevalence of The Red Cross, the plus sign ranked higher than the star, and then results followed expectations (see Appendix 1). The star image was modified in order to thwart off potential confusion over whether or not a star ranks higher than a plus sign, and this was done by connecting the star to the hash marks in a logical progression while still emphasizing the stronger probable benefit from consuming foods in the “Promising Scientific Support” category. The idea behind the system is similar to the levels of rank soldiers are given in the military and to apply it in a “badge” format. The hope is that these ranked badges would be promptly displayed directly following any health claim in a superscript position so as to not detract from the brand image companies may be trying to put forth.

The understanding of what a badge signifies has been evolving throughout the years. Generally they work to display achievement. Badges were traditionally worn on clothing, but like many things of the past they too are becoming digitized. Microsoft and Sony have implemented very successful badge achievement systems through their online gaming services (Xbox 360 achievements and PS3 trophies). The purpose of these systems is to motivate gamers to play more frequently to “unlock achievements” and earn badges that can gain respect from peers. This approach to motivation is being applied towards education. The Mozilla Open Badges project aims to make it easier to get recognition for skills and achievements that happen outside of school. Badges have come to represent an ideal combination of easily and simply displaying meaningful information.

The application of badges to probiotics can be two fold. Not only could complex scientific information be easily conveyed to consumers, but there is an incentive for scientists to collectively research new and developing probiotic strains. With placing a ranking system directly on the front of product labels, consumers have a greater ability to spend their money only on the products for which they feel they will receive the most benefit. Of course, people have varying purchasing decisions and levels of “risk” they are willing to take with new products, but the intent is to help those people make the best decisions they can. It is likely that for two similar products with different rankings, consumers will pick the one with the badge that suggests the product has the most scientific backing for their health claims. Consequently then, the quicker a probiotic strain can gain scientific backing, the more sales the product will generate. Researchers are incentivized to conduct more numerous and thorough studies on probiotics because they likely will be able to see a tangible benefit resulting from “moving up in rank.”

While badges may provide some benefit, they do not address the issue of whether or not to create a new regulatory category for probiotics. There are many other serious issues to consider besides just the labeling. Some of these issues were raised in the “Research Difficulties” and “Current Probiotic Regulation and Difficulties” sections. Also central to the problem is the question of being able to draw meaningful conclusions, or demonstrate efficacy, from probiotic clinical trials. This is largely dependent on establishing relevant endpoints for human trials and biomarkers for which to measure them. Doing so has been difficult. This is especially the case for probiotics intended to maintain current health and not alleviate a specific condition. Answering these kind of questions proves to regulatory agencies that health benefits from probiotics are real and deserving of special attention, and not just some new pseudoscience. If only a handful of probiotic strains turn out to actually be beneficial to humans then it wouldn’t make sense to have a whole new regulatory category for them. This is not expected, but the current state of knowledge makes it difficult to infer about the future.

Even when well informed it can be difficult to predict the future. Trends, patterns, and figures from the past can give a rough idea of what to expect, but these can not account for technological breakthroughs and revolutionary new findings (Shiller, 2010). This is why many forecasts are wrong as often as they are right. Their accuracy isn’t expected to get any better in a world that is changing faster than it ever has—as demonstrated by the exponential growth in computational power. The limits of computing set by vacuum tube computers were exceedingly surpassed with transistors, a discontinuous innovation. The cost of sequencing an entire genome has decreased from about $2.7 billion at the end of the Human Genome Project in 2003 to around $10,000 in 2011—far exceeding Moore’s Law—due in large part to next-generation sequencing technology (Wetterstrand, 2011). The goals of the Human Microbiome Project (HMP) are equally ambitious, and the future holds incredible possibility for characterizing the various microbial communities found in the human body.

The road map to a new regulatory category for probiotics is not entirely clear yet. Creating an incentive structure for probiotics research through badges on product labeling is the first step. New ways of measurement are needed for determining probiotic efficacy, and this likely will hinge on the analysis of the results from the HMP expected to complete in 2012. The National Institutes of Health has endorsed the rapid release of HMP-generated data, which should accelerate this process. There is a lot of gray area, but when industry can definitively prove probiotic efficacy across numerous species and strains, making probiotics a class of their own makes much more sense. This new category would ideally have an abbreviated approval process when safety is assured. The incentives are further built into the system already because the early pioneers of probiotics can make broad, general claims in any patents they may file, thereby earning revenue from future researchers who would need to take a license of their dominating patent in order to commercialize. Future probiotic research will also hopefully follow the numerous other technology examples like the Human Genome Project and exhibit marked decreases in costs to characterize individuals’ microbiomes. With limited data, only limited conclusions can be drawn from probiotic research. Creative approaches can have surprising new results, and in some cases, can revolutionize our understanding of the natural world much in the same way Robert Koch revolutionized our understanding of disease.

Appendix

1. Survey Questions and Results

Probiotics Survey

Option 1health claim example 4 Option 2Health Claim Example 1
Option 3Health Claim Example 3 Option 4Health Claim Example 2

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  1. The assignment prompt was: The Human Microbiome Project has spurred a big interest in “probiotic treatments” – the use bacteria in food, or bacteria delivered through other means, to improve or maintain human health. The regulatory environment for probiotics is very unclear, however. The FDA regulatory framework does not contemplate the role of foods in preventing disease and maintaining optimal health, so probiotic foods or dietary supplements may be regulated as drugs. Some people argue that the typical drug development process is not always appropriate for studying probiotics. Nonetheless, many people agree on the need for rules and guidance on issues such as manufacturing standards (shelf life, purity, efficacy), accurate strain characterization, and measures of safety and efficacy. Describe some of the problems regarding current FDA regulation of probiotics, and how the regulatory uncertainties influence the nature of research and product development. Analyze the arguments for a sui generis regulatory category for probiotics. Do you think a new regulatory category is a good idea, if so, why? If not, why not? Compare the difficulties of regulating probiotics with the difficulties of regulating stem cell therapies.

  2. and I got an AB on the paper.

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