03.01.11
In January, the Council for Responsible Nutrition (CRN), Washington, D.C. submitted comments to FDA regarding Investigational New Drug (IND) applications, with an emphasis on providing further clarification on dietary supplements and food components and drugs, as well as acknowledging the inherent differences between all of these products.
According to CRN, the Draft Guidance does provide clarity in some areas, including the important distinction that the clinical investigation of a dietary supplement for a structure/function endpoint does not require an IND application. However, CRN has identified several areas where the Draft Guidance leaves important questions unanswered for industry and the research community.
As the organization points out, the IND application process is specifically designed to support companies that have screened a novel molecule for pharmacological activity and acute toxicity potential in animals and wish to test its diagnostic or therapeutic potential in humans. While this framework is applicable to the drug development process, CRN says it may not be a suitable framework for research on dietary supplements and food components that are already safely consumed by millions of Americans.
According to the Draft Guidance, an IND may be required to study a dietary supplement that is currently safely consumed by millions of Americans or a food ingredient that has Generally Recognized As Safe (GRAS) status for a given use, even when the research is conducted on a healthy population. This is true even when the investigator has no involvement or interest in the commercial aspects of a product. For example, an investigator interested in evaluating a yogurt product from the grocery store that contains beneficial bacteria for its ability to prevent constipation in a healthy population would be required to file an IND. CRN believes this is incongruent with the intent of the IND.
Unlike pharmaceutical research, the majority of dietary supplement and ingredient research is not driven by industry. For a variety of reasons, including limited intellectual property protection, the majority of supplement research is supported by government grants and performed by academic researchers that are independent of industry. Because FDA guidance is aimed at industry and not academia, CRN is concerned that the Draft Guidance will go unnoticed by the academic nutrition and complementary and alternative medicine (CAM) research communities that are focused on expanding scientific knowledge and pay little attention to the complex linguistic nuances encompassed within regulatory definitions. Furthermore, they may not understand the regulatory distinctions between drugs, supplements and their intended use, and thus may be unable to appropriately design a study protocol to accurately reflect the intent of the investigation.
If all companies and independent investigators conducting clinical research on dietary supplements with the intent of studying them as drugs followed the Draft Guidance, FDA would likely not have the resources to review and process the massive number of IND applications that would be submitted. Some of this research is conducted by independent investigators who are unaware of a product’s regulatory category and therefore design studies that are appropriate to their research questions.
FDA should provide additional clarification related to IND requirements for clinical studies designed to assess “disease risk reduction” versus “prevention.” Currently, CRN asserts, there are no validated biomarkers as surrogate endpoints for “health promotion,” “wellness,” or “supporting normal structure and function” and therefore investigators by default will choose to assess effects such as lowering of blood pressure or serum cholesterol levels, or similar effects on other established surrogates, many of which may also be viewed as therapeutic effects. This, in turn, would necessitate an IND.
CRN is aware that the Center for Drug Evaluation and Research (CDER) has available an investigatorâ€initiated IND that may alleviate some of these concerns. However, it is the organization’s understanding that the Center for Biologics Evaluation and Research (CBER) does not have such a program available and the Center for Food Safety and Applied Nutrition (CFSAN) has no IND process whatsoever. CRN recommends that FDA develop a consistent IND process across all the relevant regulatory categories and consider how academic researchers will be made aware of and comply with the provisions in the Draft Guidance.
Another issue that may negatively impact dietary supplements and food components is that naturally occurring materials have inherent variability that may not fit the IND model. For example, CRN said, there can be challenges in obtaining an IND for a fish body oil product that has a twoâ€year shelf life intended for use in a fiveâ€year clinical trial. If a second lot of fish oil is introduced during the second year of the trial there may be small (but unavoidable) differences in fatty acid composition and ratios in the replacement lot. This is due to natural seasonal variability in the fatty acid composition of fish used to produce fish oil. Historically, IND application reviewers, presumably without dietary supplement expertise, have struggled to understand these practical differences between dietary supplements/food components and drugs.
To account for physical and biochemical differences between drugs and dietary supplements/food components, dietary supplement INDs, when required, should be reviewed by individuals with expertise in dietary supplements and food components, nutrition research and/or the application of CAM therapies.
DSHEA defines a dietary supplement, in part, as a “product that does not contain an article authorized for investigation as a new drug, antibiotic or biological for which substantial clinical investigations have been instituted and for which existence of such investigations has been made public.” When a company is collecting data to submit a New Dietary Ingredient (NDI) notification to FDA and studies are conducted under IND Draft Guidance and the study results are published before the product is marketed as a food or dietary supplement, then it can no longer be marketed as a food or dietary supplement. As a result, CRN explained, a product would then require FDA drug approval before being legally marketed.
In this example the company may impose a particular study design or use of therapeutic endpoints in a clinical study involving a healthy population to explore the possibility of obtaining data for a health claim petition (disease risk reduction) or marketing the product as a medical food with no intentions of marketing the product as a drug. CRN believes that the above mentioned scenario is a significant disincentive to conducting NDIâ€related clinical research under IND Draft Guidance and creates an additional legal grey area as well as an obstacle to ingredient innovation for the dietary supplement industry
Given these issues, CRN believes FDA should provide a broader list of IND exemptions for dietary supplements and food components. Greater consideration should be given to allow for exemption of products that have a history of safe use, or are currently safely consumed as a food by millions of Americans (e.g., broccoli sprouts, yogurt, etc.). Furthermore, the organization said, the final guidance should provide clarification on IND requirements for studies conducted on a dietary supplement for targeted endpoints associated with an approved health claim or a qualified heath claim.
According to CRN, the Draft Guidance does provide clarity in some areas, including the important distinction that the clinical investigation of a dietary supplement for a structure/function endpoint does not require an IND application. However, CRN has identified several areas where the Draft Guidance leaves important questions unanswered for industry and the research community.
As the organization points out, the IND application process is specifically designed to support companies that have screened a novel molecule for pharmacological activity and acute toxicity potential in animals and wish to test its diagnostic or therapeutic potential in humans. While this framework is applicable to the drug development process, CRN says it may not be a suitable framework for research on dietary supplements and food components that are already safely consumed by millions of Americans.
According to the Draft Guidance, an IND may be required to study a dietary supplement that is currently safely consumed by millions of Americans or a food ingredient that has Generally Recognized As Safe (GRAS) status for a given use, even when the research is conducted on a healthy population. This is true even when the investigator has no involvement or interest in the commercial aspects of a product. For example, an investigator interested in evaluating a yogurt product from the grocery store that contains beneficial bacteria for its ability to prevent constipation in a healthy population would be required to file an IND. CRN believes this is incongruent with the intent of the IND.
Unlike pharmaceutical research, the majority of dietary supplement and ingredient research is not driven by industry. For a variety of reasons, including limited intellectual property protection, the majority of supplement research is supported by government grants and performed by academic researchers that are independent of industry. Because FDA guidance is aimed at industry and not academia, CRN is concerned that the Draft Guidance will go unnoticed by the academic nutrition and complementary and alternative medicine (CAM) research communities that are focused on expanding scientific knowledge and pay little attention to the complex linguistic nuances encompassed within regulatory definitions. Furthermore, they may not understand the regulatory distinctions between drugs, supplements and their intended use, and thus may be unable to appropriately design a study protocol to accurately reflect the intent of the investigation.
If all companies and independent investigators conducting clinical research on dietary supplements with the intent of studying them as drugs followed the Draft Guidance, FDA would likely not have the resources to review and process the massive number of IND applications that would be submitted. Some of this research is conducted by independent investigators who are unaware of a product’s regulatory category and therefore design studies that are appropriate to their research questions.
FDA should provide additional clarification related to IND requirements for clinical studies designed to assess “disease risk reduction” versus “prevention.” Currently, CRN asserts, there are no validated biomarkers as surrogate endpoints for “health promotion,” “wellness,” or “supporting normal structure and function” and therefore investigators by default will choose to assess effects such as lowering of blood pressure or serum cholesterol levels, or similar effects on other established surrogates, many of which may also be viewed as therapeutic effects. This, in turn, would necessitate an IND.
CRN is aware that the Center for Drug Evaluation and Research (CDER) has available an investigatorâ€initiated IND that may alleviate some of these concerns. However, it is the organization’s understanding that the Center for Biologics Evaluation and Research (CBER) does not have such a program available and the Center for Food Safety and Applied Nutrition (CFSAN) has no IND process whatsoever. CRN recommends that FDA develop a consistent IND process across all the relevant regulatory categories and consider how academic researchers will be made aware of and comply with the provisions in the Draft Guidance.
Another issue that may negatively impact dietary supplements and food components is that naturally occurring materials have inherent variability that may not fit the IND model. For example, CRN said, there can be challenges in obtaining an IND for a fish body oil product that has a twoâ€year shelf life intended for use in a fiveâ€year clinical trial. If a second lot of fish oil is introduced during the second year of the trial there may be small (but unavoidable) differences in fatty acid composition and ratios in the replacement lot. This is due to natural seasonal variability in the fatty acid composition of fish used to produce fish oil. Historically, IND application reviewers, presumably without dietary supplement expertise, have struggled to understand these practical differences between dietary supplements/food components and drugs.
To account for physical and biochemical differences between drugs and dietary supplements/food components, dietary supplement INDs, when required, should be reviewed by individuals with expertise in dietary supplements and food components, nutrition research and/or the application of CAM therapies.
DSHEA defines a dietary supplement, in part, as a “product that does not contain an article authorized for investigation as a new drug, antibiotic or biological for which substantial clinical investigations have been instituted and for which existence of such investigations has been made public.” When a company is collecting data to submit a New Dietary Ingredient (NDI) notification to FDA and studies are conducted under IND Draft Guidance and the study results are published before the product is marketed as a food or dietary supplement, then it can no longer be marketed as a food or dietary supplement. As a result, CRN explained, a product would then require FDA drug approval before being legally marketed.
In this example the company may impose a particular study design or use of therapeutic endpoints in a clinical study involving a healthy population to explore the possibility of obtaining data for a health claim petition (disease risk reduction) or marketing the product as a medical food with no intentions of marketing the product as a drug. CRN believes that the above mentioned scenario is a significant disincentive to conducting NDIâ€related clinical research under IND Draft Guidance and creates an additional legal grey area as well as an obstacle to ingredient innovation for the dietary supplement industry
Given these issues, CRN believes FDA should provide a broader list of IND exemptions for dietary supplements and food components. Greater consideration should be given to allow for exemption of products that have a history of safe use, or are currently safely consumed as a food by millions of Americans (e.g., broccoli sprouts, yogurt, etc.). Furthermore, the organization said, the final guidance should provide clarification on IND requirements for studies conducted on a dietary supplement for targeted endpoints associated with an approved health claim or a qualified heath claim.
