Recent knowledge supports the hypothesis that, beyond meeting nutrition needs, diet may modulate various functions in the body and play detrimental or beneficial roles in some diseases. Concepts in nutrition are expanding from emphasis on survival, hunger satisfaction, and preventing adverse effects to emphasizing the use of foods to promote a state of well-being and better health and to help reduce the risk of disease
. In many countries, especially Japan and the United States, research on functional foods is addressing the physiologic effects and health benefits of foods and food components, with the aim of authorizing specific health claims. The positive effects of a functional food can be either maintaining a state of well-being and health or reducing the risk of pathologic consequences. Among the most promising targets for functional food science are gastrointestinal functions, redox and antioxidant systems, and metabolism of macronutrients. Ongoing research into functional foods will allow the establishment of health claims that can be translated into messages for consumers that will refer to either enhanced function or reduction of disease risk. Only a rigorous scientific approach that produces highly significant results will guarantee the success of this new discipline of nutrition. This presents a challenge for the scientific community, health authorities, and the food industry.
Functional foods macronutrient micronutrient health claim
The primary role of diet is to provide enough nutrients to meet metabolic requirements while giving the consumer a feeling of satisfaction and well-being.
Recent knowledge, however, supports the hypothesis that, beyond meeting nutrition needs, diet may modulate various functions in the body and may play detrimental or beneficial roles in some diseases. We stand today at the threshold of a new frontier in nutrition sciences. Indeed, at least in the Western world, concepts in nutrition are expanding from the past emphasis on survival, hunger satisfaction, and preventing adverse effects to an emphasis on the use of foods to promote a state of well-being and better health and to help reduce the risk of diseases. These concepts are particularly important in light of the increasing cost of health care, the steady increase in life expectancy, and the desire of older people for improved quality of their later years.
These changes of emphasis in nutrition have, over the past 10–12 y, justified the efforts of health authorities in many countries, especially Japan and the United States, to stimulate and support research on physiologic effects and health benefits of foods and food components and to authorize health claims.
In Japan, research on functional foods began in the early 1980s, when 86 specified research programs on “systematic analysis and development of food functions” were funded by a scientific fellowship grant from the Ministry of Education. Later in the 1980s and early in the 1990s, the Ministry of Education sponsored additional focal point studies on “analysis of physiologic regulation of the functions of foods” and “analysis of functional foods and molecular design.” In 1991, the Japanese Minister of Health and Welfare established Labeling Regulations for Foods for Specified Health Use (FOSHU). These foods are included as 1 of 4 categories described in Japan's Nutrition Improvement Law as “foods for special dietary use” (ie, foods that are used to improve people's health and for which claims for specific health effects are allowed).
In the United States, the Nutrition Labeling and Education Act (NLEA), which was established in 1990 and first enforced completely in 1994, allows health claims to be made for foods containing ingredients for which the Food and Drug Administration (FDA) has scientific evidence demonstrating a correlation between intake and prevention or cure of certain diseases. As of July 1997, there were 10 foods or ingredients for which the FDA had recognized correlations with risk of disease.
In the European Union, it is already recognized that to improve the competitive position of the European food and drink industry, European research expertise must be at the forefront in understanding the role of food components in modulating body functions, maintaining and improving well-being and health, and reducing the risk of major diseases.
These concepts have begun to become popular with consumers. Although there are still many people who know little about nutrition itself, consumer awareness of the subject and its relation to health is growing appreciably. Finally, advances in food science and technology are providing the food industry with increasingly performable techniques to control and improve the physical structure and chemical composition of food products, and industry increasingly realizes that functional foods add value and have a market potential for growth.
Until now, in both Japan and the United States, approaches to developing these new concepts in nutrition have been mainly product driven and likely to be influenced by local, traditional, or cultural characteristics. To be more universal, a science-based, function-driven approach is preferable because the functions and their modulation are universal. Functional food science is a new discipline that is part of the science of nutrition and is aimed at stimulating research and development of these foods by using a function-driven approach (1).
]As a working definition, a food can be said to be functional if it contains a component (whether or not a nutrient) that benefits one or a limited number of functions in the body in a targeted way that is relevant to either the state of well-being and health or the reduction of the risk of a disease (1), or if it has physiologic or psychologic effect beyond the traditional nutritional effect (2).
At a consensus meeting (Madrid, October 1998) that was the last activity of a 3-y action supported by the European Union and coordinated by the International Life Science Institute Europe, a group of European experts adopted the following working definition: “a food can be regarded as functional if it is satisfactorily demonstrated to affect beneficially one or more target functions in the body, beyond adequate nutritional effects in a way which is relevant to either the state of well-being and health or the reduction of the risk of a disease” (3).
A functional food component can be a macronutrient if it has specific physiologic effects (eg, resistant starch or n−3 fatty acids) or an essential micronutrient if its intake is more than the daily recommendations. It can also be a food component that, even though of some nutritive value, is not essential (eg, some oligosaccharides) or is even of no nutritive value (eg, live microorganisms or plant chemicals). Indeed, beyond its nutritional (metabolic requirements) value and function of providing pleasure, a diet provides consumers with components able to both modulate body functions and reduce the risk of some diseases.
PRODUCTION OF FUNCTIONAL FOODS
A food product can be made functional by using any of these 5 approaches:
Eliminating a component known to cause or identified as causing a deleterious effect when consumed (eg, an allergenic protein).
Increasing the concentration of a component naturally present in food to a point at which it will induce predicted effects [eg, fortification with a micronutrient to reach a daily intake higher than the recommended daily intake but compatible with the dietary guidelines for reducing risk of disease (4)], or increasing the concentration of a nonnutritive component to a level known to produce a beneficial effect.
Adding a component that is not normally present in most foods and is not necessarily a macronutrient or a micronutrient but for which beneficial effects have been shown (eg, nonvitamin antioxidant or prebiotic fructans).
Replacing a component, usually a macronutrient (eg, fats), whose intake is usually excessive and thus a cause of deleterious effects, by a component for which beneficial effects have been shown [eg, chicory inulin such as Rafticream (ORAFTI, Tienen, Belgium) (5)].
Increasing bioavailability or stability of a component known to produce a functional effect or to reduce the disease-risk potential of the food.
The demonstration of such beneficial effects must be based on science, however. Having a science of functional foods will be necessary to guarantee the credibility of any assertion of benefit.
FUNCTIONAL FOOD SCIENCE
]The positive effects of a functional food can be either maintenance of a state of well-being and health or reduction of the risk of pathologic consequences.
The initial step in research and development of a functional food is the identification of a specific interaction between one or a few components of this food and a function (ie, genomic, cellular, biochemical, or physiologic) in the organism that is potentially beneficial for health. This step is fundamental research and should lead to one or more proposals for hypothetical mechanisms of the identified interactions as well as to the development and validation of relevant biomarkers. With this as background, a functional effect can then be defined that must be demonstrated in relevant models. This experimental part of functional food development concludes with a new hypothesis on the relevance of the functional effect to human health. The hypothesis must be tested in strictly designed nutritional studies involving carefully chosen volunteers, and the demonstration of effects must be accompanied by a safety assessment, an absolute prerequisite for functional food development.
In any case, the health benefit of a functional food will be limited if the food is not part of the diet. In his presentation at the First East West Perspectives Conference on Functional Foods, Pascal (6) stated, “Functional foods must remain foods; they are not pills or capsules but components of a diet or part of a food pattern recognized as being beneficial for well-being and health.”
The design and development of functional foods is a scientific challenge that should rely on the stepwise process shown in Figure 1⇓. The process begins with basic scientific knowledge relevant to functions that are sensitive to modulation by food components, that are pivotal to maintenance of well-being and health, and that, when altered, may be linked to a change in the risk of a disease. Next is the exploitation of this knowledge in the development of markers that can be shown to be relevant to the key functions. Next is a new generation of hypothesis-driven human intervention studies that will include the use of these validated, relevant markers and allow the establishment of effective and safe intakes. Last is the development of advanced techniques for human studies that, preferably, are minimally invasive and applicable on a large scale.
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Stepwise process of the design and development of functional foods.
The most promising targets for functional food science are the following:
Gastrointestinal functions. These functions include those that are associated with a balanced colonic microflora, mediated by the endocrine activity of the gastrointestinal tract, dependent on the tract's immune activity, in control of nutrient (minerals in particular) bioavailability, in control of transit time and mucosal motility, and modulators of epithelial cell proliferation (7; Roberfroid, unpublished observations, 1997).
Redox and antioxidant systems. These systems require a balanced and satisfactory intake of antioxidant (pro-) vitamins as well as nonvitamin food components such as polyphenols and other natural antioxidants of plant origin. Redox activities and antioxidant protection are important for almost every cell and tissue, and their imbalance is associated with miscellaneous pathologies. Although well-founded hypotheses often exist regarding the mechanisms of action of dietary antioxidants, demonstration of their beneficial effects, except when they are consumed as components of fresh fruit and vegetables (8), remains problematic.
Metabolism of the macronutrients. This target concerns metabolism of carbohydrates, amino acids, and fatty acids and, in particular, hormonal modulation of their metabolism via insulin and glucagon balance or the production of gastrointestinal peptides. The objective of this process is to reduce the risk of pathologic effects associated with insulin resistance and cardiovascular disease; doing so will require the study of interactions between nutrient intake and regulation of gene expression [eg, the direct role of glucose or some polyunsaturated fatty acids (9) or more indirect interactions such as the reduction of hepatic lipogenesis by chicory fructans (10, 11)].
Development in fetal and early life. Both the mother's and the infant's diet can influence this development; examples are the importance of folic acid in the diet of pregnant women and the role of long-chain polyunsaturated fatty acids in the early stage of brain development.
Xenobiotic metabolism and its modulation by nonnutritive dietary components, such as some phytochemicals. Such modulations may have important implications for the control of toxicity or carcinogenicity caused by chemical contaminants present in food or the environment.
Mood and behavior or cognition and physical performance. Many questions have been raised about the effect of food components on these functions, but the border between nutritional and pharmacologic effects is not always easy to draw. Moreover, methodologies for studying such effects are generally perceived as inadequate to generate the firm quantitative data required for a reliable statistical analysis. New developments are expected in this field soon, which will make it possible to address these issues.
The present state of scientific knowledge in functional food science has been critically assessed by 6 groups of European experts (1).
COMMUNICATION TO THE PUBLIC
The science base generated by research and development in the field of functional foods will establish health claims that can be translated into messages for consumers. According to Clydesdale (2), a health claim describes “a positive relationship (ie, reduction in risk and/or lessening of an adverse physiologic or psychological condition) between a food substance in a diet and a disease or other health related condition.” With reference to the strategy for research and development, these claims will refer either to enhanced functions or reduction of disease risk (Figure 2⇓).
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Scientific basis for enhanced structure-function or disease risk-reduction claims.
A claim of enhanced function describes the positive consequences of interactions between a food component and a specific genomic, biochemical, cellular, or physiologic function without direct reference to any health benefit or reduction in disease risk. Examples include positive modulation of metabolic activities (eg, lipid homeostasis), strengthening immune functions (ie, immunostimulation), reducing the risk of oxidative stress (eg, by using antioxidants), protecting against chemical toxicity (eg, chemically induced steatosis), restoring or stabilizing a balanced colonic microflora (eg, through selective stimulation of bifidobacteria by inulin-type fructans), and improving bioavailability of nutrients [eg, of minerals by adding oligopeptides or inulin-type fructans (Roberfroid, unpublished observations, 1997)].
Research on claims of enhanced function has already led and will continue to lead to new concepts in nutrition. Examples of such new concepts are prebiotics and synbiotics, colonic foods, and bifidogenic factors (12). Reduction in disease risk involves lowering the risk of pathologic effects or diseases by consuming a specific food components or ingredients. Examples are food components that may reduce the risk of cardiovascular disease, cancers, infections (eg, intestinal infections), atherosclerosis, liver disease, diarrhea, constipation, osteoporosis, or diseases associated with insulin resistance syndrome (eg, type 2 diabetes or obesity). Even though it will depend on the particular disease risk to be reduced, the demonstration of such health effects remains a difficult task that requires long-term experiments, the final results of which are difficult to predict and often hard to interpret.
In the case of some recent long-term studies on effects of antioxidant vitamins on lung cancer, a protective effect was anticipated but the opposite was actually found (13). This finding reinforces the importance of using a careful scientific approach based on a sound hypothesis and reasonable evidence of the mechanism of the health response expected. Both for enhanced function and reduction of disease risk, demonstration of an effect in humans will always be required in nutrition studies, but the protocols and evaluation criteria will not necessarily be those presently used in clinical studies for drug development.
The target population for these nutrition studies is, in most cases, “healthy persons” or “persons supposedly healthy” for whom the usual diet will be modified to demonstrate a significant change (statistically but, perhaps more important, biologically) in variables or biomarkers indicative of a state of good health. In the vast majority of these cases, these variables or biomarkers have yet to be discovered and validated.
PROCEDURES FOR AUTHORIZATION OF CLAIM
If a primary objective of functional food science is to contribute to the improvement, maintenance, and reinforcement of the health of consumers via a better diet, consumers and those who make recommendations to consumers have the right to require guarantees about the reliability of claims and the scientific data supporting them. Health authorities, in collaboration with the food industry and academia, will thus have the responsibility to elaborate procedures for authorizing claims that meet these legitimate requirements. Such an authorization can be given either by reference to a “positive list” or after scientific review of a file containing scientific information. Most of this information will have been published in peer-reviewed journals and will have shown a specific, biologically significant, and beneficial health interaction with one or a few functions in the body, leading either to maintenance (or possibly improvement) of a state of good health or reduction in the risk of a disease.
The establishment of a positive list and the evaluation of the dossiers containing all scientific data available, as well as the elaboration of the scientific requirements, must be made by a multidisciplinary expert committee. This committee should establish a constructive and confidential dialogue with the scientific representative of food industries with the objective of recommending, a priori, the most relevant protocols to demonstrate effects that could support a claim. Authorization for using a claim should also include a clear definition of the context as well as the limits of its communication to consumers. In particular, the dose necessary to cause a particular effect should be clearly identified on the label of each functional food for which the claim is authorized so as to make clear to consumers what portion of this dose they will be taking when consuming a given food product.
The development of functional foods provides a unique opportunity to contribute to improvement of the quality of the food offered to consumers who want to benefit their health and well-being. Only a rigorous scientific approach producing highly significant results will guarantee the success of this new discipline of nutrition. It is clearly a challenge for the food industry. However, before being considered an economic challenge, it is and must remain a scientific challenge. It is also a challenge for the health authorities because they need to elaborate new rules and new procedures that will be successful only if they rely on science in a constructive dialogue with all the relevant partners (ie, researchers in basic science, nutritionists and dietitians, and scientists in industry).
The major challenge to all these partners is to give consumers guarantees that these new food products not only are safe and based on research but also are products that will allow consumers to better control their health. It is also a challenge for nutritionists to include most of the new information in basic biological sciences in the development of new products and, at the same time, to develop new guidelines for better nutrition.
There has been significant public debate about the susceptibility of research to biases of various kinds. The dialogue has extended to the peer-reviewed literature, scientific conferences, the mass media, government advisory bodies, and beyond. Whereas biases can come from myriad sources, the overwhelming focus of the discussion to date has been on industry-funded science. Given the critical role that industry has played and will continue to play in the research process, the International Life Sciences Institute (ILSI) North America Working Group on Guiding Principles has, in this article, proposed conflict-of-interest guidelines regarding industry funding to protect the integrity and credibility of the scientific record, particularly with respect to health, nutrition, and food-safety science. Eight principles are enumerated, which specify the ground rules for industry-sponsored research. This article, which issues a challenge to the broader scientific community to address all bias issues, is only a first step; the document is intended to be dynamic, prompting ongoing discussion and refinement. In the conduct of public/private research relationships, all relevant parties shall 1) conduct or sponsor research that is factual, transparent, and designed objectively, and, according to accepted principles of scientific inquiry, the research design will generate an appropriately phrased hypothesis and the research will answer the appropriate questions, rather than favor a particular outcome; 2) require control of both study design and research itself to remain with scientific investigators; 3) not offer or accept remuneration geared to the outcome of a research project; 4) ensure, before the commencement of studies, that there is a written agreement that the investigative team has the freedom and obligation to attempt to publish the findings within some specified time frame; 5) require, in publications and conference presentations, full signed disclosure of all financial interests; 6) not participate in undisclosed paid authorship arrangements in industry-sponsored publications or presentations; 7) guarantee accessibility to all data and control of statistical analysis by investigators and appropriate auditors/reviewers; 8) require that academic researchers, when they work in contract research organizations (CRO) or act as contract researchers, make clear statements of their affiliation; and require that such researchers publish only under the auspices of the CRO.
It has been said that “scientific ‘truth’ is the primary aim that all should pursue in the jungle of academic-industry interactions” (1). The point of scientific endeavor, in the first place, is and should be, the pursuit of truth—nothing more, nothing less—irrespective of financial or other interactions. It goes without saying that seekers of truth must not impose preconceptions on the method or result of their search: they must not have ulterior motives. Throughout modern history, scientists have been guided by rules that ensure the integrity of the pursuit of truth, rules that continue to evolve as the research and communication landscapes change. The purpose of this article is to articulate, in the sophisticated, industrialized, modern world in which we find ourselves, principles defining and protecting the integrity and maintaining the credibility of the scientific record, particularly that part of it devoted to health, nutrition, and food-safety science.
The agricultural, food, and nutrition sciences have come to be a crucial part of evolving health research, which, in turn, plays an ever-growing role in improving the human condition. Although regarded as important determinants of human health, agricultural practices, food processing and safety, and nutritional status do not receive the same attention and funding from the federal research agencies as biomedical research does. Federal funds allotted to agricultural, food, and nutrition research amount to ≈$1.8 billion annually (out of a total US Department of Agriculture research budget of $2.3 billion),
with most of this focusing on agricultural production; in contrast, $28.6 billion is appropriated to the National Institutes of Health (2). Industry-funded research projects, large and small, account for a large proportion of all food science and nutrition research (3–5), both for obvious and nonobvious reasons.† United States' law places the responsibility for product safety and for the truthfulness of label claims on the manufacturer. Clearly, it is in the food industry's interest to conduct the research necessary to meet the legal requirements as well as to improve food-product healthfulness, safety, accessibility, taste, cost, attractiveness, etc. Most of this research falls outside the mission of traditional federal funding agencies and would not be done without food industry support. Pursuant to an extensive web of laws and regulatory requirements concerning food and food ingredients that have evolved over the past century, industry scientists and academic researchers who work with industry strive to enhance food quality, studying everything from the safety of ingredients to the evidence in support of health claims that appear on food packaging.
The rationale for food industry funding of research may be less obvious in areas such as microbiology (6),‡ toxicology (7–9),§ nutrient bioavailability (10, 11), and fortification (12)—all of which lead to enhancement of human health and to research on animal breeding and agricultural efficiency, which helps to feed more people. Some such research will be conducted by industry, in-house, whereas other projects will be contracted out to academic institutions or government or contract research laboratories. Scientists, especially novice researchers, conducting investigations in any of these settings need principles on which to rely while conducting their research ethically and with integrity. Clearly, it is essential to preserve the integrity and credibility of food and nutrition science for the benefit of public health and understanding.
In recent years, a growing body of literature has evolved on the subject of conflicts of interest and their potential influence on the integrity of researchers and the scientific record. In these discussions, conflicts are typically treated as disqualifying factors in scientific papers and research; that is, scientists with conflicts of interest are viewed in the literature as being at least partially integrity-compromised, and, even with complete and open disclosure, are regarded, at least to some extent, as of suspect scientific credibility. It is hoped that this article will define and clarify the highly complex issues involved in questions of conflict and scientific bias, particularly with regard to the portion of research funding that originates from the food industry.
In the interest of beginning this crucial dialogue in a sharply defined and dispassionate manner, the focus of this article will be limited to only one very specific issue and its relation to bias: financial conflicts of interest, specifically funding-based conflicts. It must be pointed out that there is a potential for all funding, regardless of source (eg, public, private, government, or industry), to bias behavior, unconsciously or otherwise. The focus of the current article will be on the management of potential bias from industry funding of science. Our goal is to separate monetary considerations from the science—including research design, execution, reporting, publishing, and other factors.
From its beginning, the food industry has concerned itself with researching food products and ingredients from the perspective of safe and efficient delivery of food to a rapidly expanding population. Before World War II, the overwhelming bulk of food research was funded and carried out by food-industry scientists; there has been little public funding of food safety and nutrition research. It was the evolution of American society from the laissez faire environment that existed during the industrial revolution to the complex public/private sector mixed economy of the more recent past that transformed research funding and higher education in general.
Although the food industry first entered the era of managing financial conflicts in the late 18th century, with the development of proprietary technologies to enhance food preservation and safety, the post-World War II period saw an exponential increase in the administrative challenges of research funding. For example, the number of patents awarded to universities or academic researchers increased by a factor of 10 in the past 2 decades of the last century (13). Similarly, federal funding of research increased from $405 million to $1.7 billion in a single decade (1960–1970) after the launch of the space race between the United States and the Soviet Union (14).
In the decades after World War II, in addition to the significant increases in government funding of university research, the United States experienced, in general, rapid evolution of science and technology, transformation and consolidation of agricultural production, and the steady growth of industry, especially those companies involved in public health, eg, medical/pharmaceutical, chemical, and food industries. In late 1980, the US Congress passed the Bayh-Dole Act, with the specific intention of stimulating the transfer of technology from government-funded university research to the private sector (15). This legislation has not been without controversy—both over issues concerning the diversion of university faculty from basic research and conflict of interest concerns due to the resulting university-industry partnerships.
The research community and individuals involved in health communications and public policy advocacy became increasingly concerned about the possibility that exogenous interests might influence published results of scientific research (16, 17).ll By late 2000, this concern had become heightened around medical/pharmaceutical practice: a number of articles appeared in the major medical journals (18, 19) that explored the financial relations of the pharmaceutical industry and physicians and their possible effect on physicians' decisions about patient treatment, researchers' decisions concerning study design, companies' interference in publication, and public health policy in general. Medical and other scientific journals began establishing rules for disclosure of financial conflicts in an attempt to manage them.
In succeeding years, concern broadened to include other industries, more recently the food industry, with authorities questioning how financial conflicts might impinge on the outcomes of health, nutrition, and food-safety research. It was generally acknowledged that the issue was complex and not susceptible to narrow or inflexible remedies, but that has not deterred some groups from concluding that industry-funded science is inherently biased (20, 21). These groups demanded that all industry-funded research, whether conducted at contract research facilities or at universities, be denied consideration in the formulation of public policy and that scientists who have conducted industry-funded research be barred from serving on public policy advisory committees (22). It is this article's contention that such efforts are helpful neither to the public nor to the scientific community. Industry funding, although a major component of the scientific landscape, is only one piece of an extremely complex research environment. The twin issues of financial conflict and bias demand a more reasoned approach and skillful management.
DEFINING THE ISSUE
First, conflicts of interest are not inherently determinants of bias. Even a massive multiplicity of conflicts, in and of itself, carries with it no certainty of bias. Although many definitions exist for conflict of interest and bias, the simplest of definitions suffice.
Conflict of interest
“A conflict of interest is ‘a conflict between the private interests and the official responsibilities of a person in a position of trust.' A conflict of interest thus arises when a person has to play one set of interests against another” (23).
Per the online Oxford English Dictionary, bias is an “inclination or prejudice in favour of a particular person, thing, or viewpoint” (24). “A cognitive bias is something that our minds commonly do to distort our own view of reality” (25).
Or, more rigorously, bias is a deviation of either inferences or results from the truth, or any process leading to that kind of systematic deviation. This includes tendencies by which data are reviewed or analyzed or interpreted or published in a way that yields conclusions that deviate systematically from the truth (26, 27).¶
For example, for researchers, a conflict might describe a situation in which a funder has offered financial incentives for research and hopes for a particular research result; it might also describe a situation in which the researcher, for philosophical, religious, or professional reasons, wishes to achieve a certain result. Neither situation necessarily results in a biased result, which would depend on a measurable deviation of research results from “the truth,” although much of the literature regrettably confounds bias and conflict. For that matter, much of the literature confuses conflict with a particular kind of conflict—financial. Unfortunately, even if all conflicts were banished forever, there would still be myriad sources of bias.
For example, the following well-known forms of scientific and publication bias exist (28):# sample-selection bias, sample-size bias, data-collection bias, data-quality bias, statistical-analysis bias (29), confounding-variable bias, and publication bias (30). These are just a few of the more commonly encountered pitfalls leading to skewed research conclusions, but these scientific sources of bias may be easier to identify than other cognitive and emotional causes that have nothing to do with the formal research process. Consider the following possible sources of bias: one's previous body of work; one's desire for fame and respect among peers (or, alternatively, the desire to achieve iconoclastic stature); religious bias; ethical or values-based bias; philosophical bias; political bias; one's nationality or ethnicity; pressure to publish (31);** pressure to win prizes; fear of losing one's job or position; highly personal matters, such as one's physical or mental health issues or one's family's health; the pernicious effect of pack behavior or “group think” facilitated by social or professional networks, either in the physical world or in cyberspace (blogs, websites, chat rooms, list serves, and other communication tools of the Internet); financial or funding bias resulting from all kinds of financial incentives, including gratuities, bribes, grants, free trips, gifts, and cash prizes; and the desire to please one's source of funding, either unconsciously or deliberately.
The multiplicity and variety of sources of bias in research and in public health communications generally are extensive, complex, and yet of major importance to scientific research, the integrity of individual study, and the body of scientific literature as a whole. Strategies must be developed to address and manage all sources of bias, whether technical, statistical, cognitive, or emotional in origin. These are critically necessary, not just for the scientific community, but also for the well-being of the public. The interpretation of health research and the promotion of public policies resting on that research are far too important to be based on formulas that would address conflicts at the price of excluding the input of a large proportion of food-safety and nutrition scientists.
EXISTING CHECKS ON BIAS
As far as scientific research and communications are concerned, several checks exist to ensure adherence to good practice and to avoid biased conclusions. Of course, replication and coherence of scientific findings are the major mechanism by which bias in research is controlled. This section is intended to summarize postresearch control mechanisms. First and foremost is the system of scientific peer review that is built not only into publication in scientific journals, but also into the promotion and tenure decisions for individual faculty conducting research at colleges and universities. Governance and review processes of academe exercise oversight, particularly on industry-funded research projects. Charges of irregularities, errors, and outright scientific fraud are usually investigated by the academic institutions where the research is conducted. However, in one recent noteworthy case, a distinguished nutrition researcher resigned his university position 9 y after initial charges of fraud were filed in connection with his infant-formula study. In the university's subsequent report, the authors recommended that the government monitor scientific misconduct through a new national agency “charged with all aspects of science, irrespective of funding sources, public or industry [emphasis added]” (32).
Most importantly, peer pressure serves as a check on bias, ie, the peer pressure of meetings, conferences, e-mail listservs, and discussion boards run by scientific colleagues and, especially, the process of peer review, particularly relied on by the thousands of scientific journals around the world and other organizations (33).†† For more than a century, peer review has served to provide a rigorous framework by which research papers and articles can be evaluated before their general dissemination—although not foolproof, scientists regard the process as a reliable safeguard against errors, biases, and scientific misconduct. However, in recent months, a robust debate has been generated about peer review and whether it needs to be refined (34, 35). Donald Kennedy, the former Editor-in-Chief of Science for the Journal of the American Association for the Advancement of Science (AAAS), has offered an eloquent defense of the current peer review process as “a fair system of evaluating and publishing scientific work—one that offers high confidence in, though not an absolute guarantee of, the quality of the product” (36).
If all of these checks fail, a governmental oversight structure exists within the granting agencies. For example, the Office of Research Integrity in the Department of Health and Human Services sets policies for government research grants, establishes reporting standards, and investigates misconduct (37). National and local volunteer health organizations review health science as it unfolds. Finally, the following checks on bias exist: science writers and journalists, who attend scientific conferences, digest new studies, and communicate them to the public; science associations, such as the National Science Foundation and the National Academies of Science, which regularly review new research and publish articles that are, in turn, read and commented on by member scientists; Congressional hearings reveal and publicize the real or perceived biases arising from too-close relations between industry and academia; and, ultimately, public disgrace occurs when research is revealed as deeply flawed.
In any case, given the increasingly broad and complex nature of scientific research and communications, additional recommendations are appropriate for managing the extremely complex issues of financial conflicts and potential bias.
PROPOSED GUIDELINES ON INDUSTRY FUNDING OF RESEARCH
Although funding, whether through the private or public sector, does not automatically introduce bias into scientific research, it is nonetheless prudent to address both the possibility of bias and the perception of it through explicit guidelines. On the basis of work commissioned by the ILSI North America Working Group on Guiding Principles, a series of proposals was developed to manage potential biases resulting from conflicts of interest between research investigators and companies wishing to fund their work.
It is our view that disclosure is an essential, but no longer a sufficient, measure to safeguard research from undue influence exerted by funding organizations. Managing conflicts, case by case, is the requisite step, ie, procedures need to be established, such as the following guidelines, to ensure research integrity. This should apply across the array of mechanisms through which research is funded currently: in intramural industry and government laboratories; in sponsored grants and contracts; and in cooperative agreements, Cooperative Research and Development Agreements (CRADAs), and “platforms” funded jointly by governments and industry, as is the case in the European Union and Australia. Whereas there may be a multitude of mechanisms by which research is funded, designed, conducted, and communicated, these guidelines should be adhered to by all parties, in all respects, in the spirit of openness and honesty that are the aim of this article (see the footnote to guideline 2 below).
It is also our view that industry participation in the effort to disclose and manage financial conflicts of interest is crucial. Future university-level science students will find their way into either private-sector research occupations or public-sector careers. All need a set of principles to guide their interaction with funding organizations, whether public or private, just as those organizations need principles to guide them in their interactions with academic scientists. Consequently, we propose the following guidelines to serve as a checklist to achieving unbiased research results from industry-funded activities—just as they might be useful guidance in public- or foundation-funded projects (38).‡‡
In the conduct of public/private research relations, all relevant parties shall:
1) Conduct or sponsor research that is factual, transparent, and designed objectively, and, according to accepted principles of scientific inquiry, the research design will generate an appropriately phrased hypothesis and the research will answer the appropriate questions, rather than favor a particular outcome;
2) Require control of both study design and research itself to remain with scientific investigators;§§
3) Not offer or accept remuneration geared to the outcome of a research project;
4) Ensure, before the commencement of studies, that there is a written agreement that the investigative team has the freedom and obligation to attempt to publish the findings within some specified time frame;llll
5) Require, in publications and conference presentations, full signed disclosure of all financial interests;
6) Not participate in undisclosed paid authorship arrangements in industry-sponsored publications or presentations;
7) Guarantee accessibility to all data and control of statistical analysis by investigators and appropriate auditors/reviewers;¶¶
8) Require that academic researchers, when they work in contract research organizations (CRO) or act as contract researchers, make clear statements of their affiliation; and require that such researchers publish only under the auspices of the CRO.
IMPORT AND IMPLICATIONS OF THE GUIDELINES
Obviously, guidelines are just … guidelines. They are not law, but if the research community embraces them, or even embraces their spirit, we believe there will be a profoundly beneficial effect on the quality and integrity of research that will encourage responsible oversight and stewardship of scientific research by all funding organizations. Following the guidelines will undoubtedly lead to closer and more open communication between funding bodies and researchers, resulting in a new spirit of collaboration. Still, it must be stressed that each organization wishing to adopt these guidelines needs to develop its own quality-control mechanism to ensure good compliance.
A strong peer-review system coupled with open declarations of research sponsorship in all scientific communications is a mandatory prerequisite for these guidelines to be effective. The second prerequisite is that university and industry policies be promulgated to address the issues raised in these guidelines regarding control of the design and conduct of the research and its publication. It is the responsibility of both the funding entity and the researchers being funded to adhere to the guidelines; existing oversight structures are also encouraged to endorse and adhere to them. Furthermore, it should be understood that failure to embrace the guidelines will raise serious questions about any research project so conducted.
It has been suggested that, in the past, industry-funded research may have had a bias toward results favored by the food industry (21, 43). The authors of one publicized study (4) who reached this conclusion proposed several explanations: 1) food industry companies may wish to demonstrate the superiority of their products to those of their competitors, 2) investigators are influenced by their funding when formulating their research design and/or hypotheses, 3) industry sponsors of research may suppress unfavorable results, 4) authors of scientific reviews may deliberately bias their searches and interpretations to the benefit of their industry funders, and 5) scientific reviews may disproportionately represent studies “arising from industry-supported scientific symposia.” Such criticism overlooks the fact that most university research is basic in nature and that companies frequently enter into research agreements with university faculty at a point at which preliminary experiments (whether conducted in the faculty member's laboratory or in the company's laboratory) have established the proof of concept and, therefore, the likelihood that the research will have positive results is enhanced.
Notwithstanding the obvious observation that scientific reviews conducted by nonindustry-supported authors are also subject to many potential biases, the 8 principles articulated in this article address all of these possible sources of skewed research. Indeed, if these principles are vigorously adopted as the guidelines they are intended to be, there would be virtually no reason to quarrel with a research conclusion except to dispute the science itself.
In fact, the 8 principles articulated herein are intended to provide a clear statement of responsibility on all sides—those that are funding activities as well as those being funded—when academic institutions or academicians are recipients of industry funding for research, publication, or presentation. The principles are intended to offer guidance for the food industry and academic researchers who work with industry, when industry-funded research projects are involved. They may be thought of as a checklist to help ensure insulation of any research project from the provision of the resources enabling the project.
Finally, the guidelines are offered as only a first step in creating a firewall against bias in research: this article is intended to be a dynamic document, prompting ongoing discussion and refinement of the guidelines it presents.
A CHALLENGE TO THE BROADER COMMUNITY
The objectives outlined above may be worthy, though not easy to achieve. However, these principles can also serve as an invitation to the broader scientific, science communications, and public policy communities to embrace similar pledges to immunize their work against the myriad potential sources of bias—nonfinancial as well as financial conflicts. The present article was necessarily confined to one relatively small aspect of an extremely complex issue. However, future discussions could be much wider ranging and much more comprehensive if they embrace all sources of bias and expand the focus from the very narrow issue of potential bias due to financial conflicts of interest.
Consider the extensive list of biases touched on at the end of the section on definitions above: how constructive might it be for the broader scientific, communications, and public policy communities to adopt guidelines to ensure that their work is free from bias? For example, such guidelines might include pledges of transparency (eg, voluntary disclosure of all previous research, published articles, and policy positions that might influence present research, published articles, and policy positions), disclosure of sources of funding (both of the project at hand and overall funding), and disclosure of other potential biases (eg, philosophical, religious, ethical, or political orientation; intention to publish or otherwise garner public or political authority or power through publicity; and previously announced public positions that might be relevant to the work at hand).
Other researchers or groups that are not supported by the food industry (eg, nongovernmental organizations, foundations, and advocacy and consumer groups) might include in their public communications appropriate promises that their work, to the extent possible, is open and objective (not skewed to a particular conclusion or philosophical view) and is controlled by the researcher or cited authority (rather than by a hidden funder or interested party). The checklist provided in the section above on the guidelines' import and implications might prove helpful in designing similar guidelines for other groups.
It is important to state explicitly what this paper has excluded from consideration. Notwithstanding that all scientific research, whether funded by industry or not, should be subject to the same ethical rules, discussion of all of the following potential institutional sources of bias that can affect the integrity of the published scientific record was specifically excluded from this article: foundation-funded research, government-funded research, and work by academicians on advisory panels to industry, grant panels, government advisory panels, nongovernmental organization panels, and voluntarism on behalf of professional societies.
This is a short list of organizational work and funding situations that routinely pose profound challenges to the independence and integrity of scientific research—the list could certainly be lengthened. All of these potential sources of bias are outside and beyond the scope of this article, but it is suggested that future articles explore the ramifications of inappropriate influence of such organizational bias on research or public policy. It is strongly urged that future investigations into this area be sufficiently broad to include the many nonscientific and other institutions that routinely play a communications role in science-based public policy.
We could lament that this entire effort to manage conflicts of interest and to banish bias in science, is, alas, insufficient. It would be easy to complain that the financial and other pressures on research are too great to channel them neatly. Furthermore, some will argue that a mere set of guidelines cannot immunize science from error, misinterpretation, or deliberate miscalculation. We deliberately left aside, for the time, the matter of enforcement mechanisms for these or any guidelines, believing instead that achieving a consensus on best practices in managing conflicts must certainly come before establishing sanctions for failing to adhere to best practices. As professional scientific societies, industry groups, and other organizations that engage regularly with researchers adopt a common set of rules by which to manage these difficult issues, enforcement of guidelines will automatically become increasingly less problematic.
In the end, management of conflicts of interest, and, for that matter, management of scientific biases altogether, is a matter of consensus building, not enforcement. Should we indulge in more of the self-recriminations that have gone on for far too long or should we construct a workable start to a solution? The choice is obvious: it is time to act. The interpretation of health research and the promotion of public policies resting on that research are far too important for us not to address and manage the myriad potential biases that can intrude. Let this effort be a start.