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This article reviews the legal and regulatory definitions of medical food with emphasis on the Distinctive Nutritional Requirements (DNR) imposed by a disease that differs from the requirements for the normal healthy population. The author addresses clarifying the term DNR, identifying and validating more sensitive biomarkers to help explain variability in individual nutrient needs and encourages dialogue among nutritional scientists and researchers in public and private sectors to develop innovative nutritional products with greater confidence for the support the DNR of patients.
As understanding of the relationship between diet, lifestyle, genetics, the environment and health increases, so does the need for scientific advances in related analytic fields to help document, validate and replicate clinical study results used to substantiate claims made about new, innovative products. In contrast to well-defined disciplines, such as biochemistry, physiology, microbiology or immunology, the field of nutrition integrates many elements from these disciplines into a holistic, systems approach. Some may consider the term “nutrition” to be narrowly constrained to the food and dietary patterns used to fuel the body, with a prerequisite contribution of essential nutrients, unable to be synthesized by humans, yet critical for normal functioning of cells, tissues and organs.
Considerable effort has been devoted to establishing the Dietary Reference Intake (DRI) for macronutrients, several vitamins and minerals, water and electrolytes based on the best available scientific evidence of nutrient needs by healthy populations segmented by age and gender.1 Other researchers study components of food, ingredients, even spices and herbal products to better understand what molecules or pathways might be responsible for benefits observed in populations and individuals who consume certain food products as part of their traditional diet or for therapeutic purposes.
When a disease process interferes with any aspect of those systems collectively contributing to the normal physiology and metabolism of a patient, their nutritional status could be compromised. Interference in any - or multiple - systems involved in the processes of ingestion, digestion, absorption, transportation, utilization and excretion of nutrients may result in altered nutrition for the patient. When needed, alternative approaches that compensate for impaired systems could include an alternate route of nutrient delivery (e.g., feeding tube when the oral-duodenal path is impaired), simplified ingredients (pre-digested proteins or peptides, shorter chain lipids) or active forms of vitamins (e.g., 1,25 dihydroxycholecalciferol or 5-tetrahydromethyfolate).
The only classification of food permitted by FDA to claim suitability for patients with a disease is “medical food.” As suggested above, when a disease impairs normal nutrient intake/processing, specially formulated products with easy to absorb ingredients may still enable the patient’s nutritional needs to be met. In other cases, for instance when genetic abnormalities result in an Inborn Error of Metabolism (IEM) such as phenylketonuria, highly specific formulas must limit certain nutrients to very low levels to prevent toxicity caused by a defective metabolic pathway.2
In the US, medical food was first defined as part of amendments to the Orphan Drug Act of 1988 and regulations were formally promulgated by the US Food and Drug Administration’s Center for Food Safety and Applied Nutrition (CFSAN) as part of the Nutrition Labeling and Education Act (NLEA) of 19913. The definition was provided in the context that medical food was exempt from traditional nutrition labeling, so long as certain criteria were met. The regulatory wording in the Code of Federal Regulations (CFR) quotes the statutory language paragraph included in the Orphan Drug Act, but continues, elaborating on five specific criteria that must all be met to qualify for the medical food exemption from labeling required of all other food.4 When referring to medical foods and their unique nutritional relationship supporting a patient with a disease, many companies developing innovative nutritional products selectively focus on the shorter Orphan Drug Act wording rather than the CFR text that, while going into more detail more narrowly constrains the potential category. To better illustrate this point, the text of 21 CFR 101.9(j)(8) is provided below:
(j)(8) Medical foods as defined in section 5(b) of the Orphan Drug Act (21 U.S.C. 360ee(b)(3)). A medical food is a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.
A food is subject to this exemption only if:
(i) It is a specially formulated and processed product (as opposed to a naturally occurring foodstuff used in its natural state) for the partial or exclusive feeding of a patient by means of oral intake or enteral feeding by tube
(ii) It is intended for the dietary management of a patient who, because of therapeutic or chronic medical needs, has limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or who has other special medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the normal diet alone
(iii) It provides nutritional support specifically modified for the management of the unique nutrient needs that result from the specific disease or condition, as determined by medical evaluation
(iv) It is intended to be used under medical supervision
(v) It is intended only for a patient receiving active and ongoing medical supervision wherein the patient requires medical care on a recurring basis for, among other things, instructions on the use of the medical food.
In the above published regulation, both the statutory wording from the Orphan Drug Act that defined the term “medical food” and the elaborated criteria that must be met are spelled out. It is worth noting the phrase used by Congressional lawmakers:
“…which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements…are established…”
was altered slightly when regulations were written three years later to:
“…It is intended for the dietary management of a patient who, because of therapeutic or chronic medical needs, has limited or impaired capacity to ingest, digest, absorb or metabolize ordinary foodstuffs or certain nutrients, or who has other special medically determined nutrient requirements …”
The shift in wording from “dietary management of a disease” to “dietary management of a patient” has been the subject of debate for several years, since only a drug is permitted to claim to prevent, treat, mitigate or cure a disease and then only when safety and efficacy are demonstrated by extensive and costly clinical trials. Food, including dietary supplements and medical food, is not to be used to “treat the disease,” but rather to support the diseased patient’s nutritional needs. When body systems are impaired because of a disease or condition (as detailed in the CFR), a medical food may properly be formulated to compensate. However, the phrase that remains a central point of contention between companies developing innovative nutritional products for patients and FDA’s enforcement warning letters challenging a product’s claims is Distinctive Nutritional
The Orphan Drug Act uses DNR as a hallmark of eligibility for medical food definition, if they have been established for the disease or condition. CFR uses “…unique nutrient needs that result from the disease or condition…” or for the dietary management of the patient “…who has other special medically determined nutrient requirements …”
Current FDA regulations and non-binding Frequently Asked Questions about Medical Foods; Second Edition, Guidance for Industry5 do not specifically define or elaborate on scientific criteria used to determine whether a disease or condition imposes DNR on a patient. However, it does discuss another condition of DNR in patients with diabetes, saying that their dietary requirements associated with their disease can be managed by modification of the normal diet, alone, effectively ruling out diabetes as a disease for which medical foods could be formulated.
A clear, evidence-based definition of what is meant by the terms “distinctive nutritional requirement” of a patient and “unique nutrient needs” or “…other special medically determined nutrient requirements…” is needed. In addition, further elaboration is required for the phrase, “…the dietary management of which cannot be achieved by the modification of the normal diet alone.” What constitutes “the normal diet” today? Does that include dietary supplements or are they truly intended to “supplement the normal diet”? What if dietary management is possible, but actual patient compliance with such recommendations is poor? Could a medical food then be formulated in line with diet modifications required, but in a format or composition that makes it possible or more desirable for the patient to accept and follow the defined dietary modification? Kossoff recently reported the true patient benefit from a ketogenic diet or modified-Atkins diet in patients with intractable epilepsy.6 When multiple drugs were unable to reduce seizures in patients, a highly restrictive, yet physically possible, dietary regimen that limited carbohydrates, but increased fat to generate ketone bodies dramatically reduced seizures, and hence in particular for pediatric patients improved normal development and better participation in regular family life. Long term adherence to the diet was the difficult part. If specially formulated foods were developed allowing patients to maintain their dietary restrictions and provide portability or improved palatability, there appear compelling reasons to recognize them as a medical food and to subsequently provide the healthcare professional with a useful tool for better disease management through targeted nutrition.
In 2014, the American Society for Nutrition (ASN) created the Food for Health Working Group. It is comprised of representatives from government, academia and industry who were willing to address some of the nutritional science aspects outlined above. During ASN’s annual meeting in 2017, this group sponsored a satellite program to begin a broader dialogue on the establishment of science-based distinctive nutritional requirements for disease states, which would then become the topic of a workshop being planned by the Food and Nutrition Board of the National Academies of Science, Engineering and Medicine (NASEM). With financial support from FDA CFSAN, three key institutes of the National Institutes of Health (NIH) (Office of Dietary Supplements, National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases), Health Canada, ASN, Academy of Nutrition and Dietetics and Crohn’s and Colitis Foundation, this workshop was held 2-3 April 2018 in Washington, DC. The full program agenda, video, slides of all presenters and the summary report is publicly available.7,8
The workshop highlighted how the process for setting DRIs for nutrients depends on population data, and takes a statistical approach in setting recommended dietary levels of nutrients to avoid deficiency diseases. Individual variation in response to a given dose is large, but only the statistical mean is used. The premise that this value is representative of the “healthy, normal, population” is compounded by the fact that more than half of the US population has some form of chronic medical condition.9 DRIs might not be the most appropriate reference to address the possibility that patients with some form of disease may have DNR different from the normal population, as a result of their disease or its treatment. Examples of IEMs and the very different nutritional restrictions of patients were discussed, creating a true DNR versus the general public. Other examples of disease-induced nutrient deficiency and conditionally-essential nutrients or their active metabolites not needed in the same amounts by healthy people also were presented.
There is an ongoing need to develop and validate biomarkers and clinical tests that may be more sensitive for detecting sub-optimal nutrient levels in the circulation or within target tissues themselves. In contrast to simply avoiding frank deficiency symptoms, biomarkers may indicate whether a disease might alter physiologic or metabolic systems that, with special formulations, might be susceptible to compensatory pathways. Such advanced analytics also could explore how markers of genotypic variability could potentially lead to documenting different nutrient requirements, at either the cellular or sub-cellular level, and are currently attributed only to inter-subject variability using more crude markers.
Finally, new approaches to designing and conducting human clinical trials are becoming more widely accepted, with the parallel expansion of personalized medicine and personalized nutrition that leverage “big data,” including electronic health records and other patient attributes and symptoms, including “well-being.” Such “N of 1” trials may sequentially follow a single patient with control and treatment intervals while tracking their response to both using clinical tests, medical and electronic devices, questionnaires and other objective and subjective measures.10 As they become more widely accepted by regulatory agencies for establishing the safety and efficacy of new therapies—at a much faster pace and with lower cost—the value of nutritional products, specifically medical foods, may become clearer.
Another NASEM Food and Nutrition Board activity conducted an extensive, joint US-Canada review of the process for establishing DRIs and investigating how disease endpoints might be factored into future committee activities. It is important to note the workshop’s consensus report stated: “DRIs are guides for achieving safe and adequate intakes of nutrients and other food substances from foods and dietary supplements.”11 The report went on to further define the term used: “Food substances consist of nutrients that are essential or conditionally essential, energy nutrients, or other naturally occurring bioactive food components” with the caveat that “future DRI committees might find it useful to review and revise this definition.”12 By expanding the recognition that bioactive food components may be found to be as important as “nutrients” in health and disease, there is great opportunity, and critical need, to re-consider what constitutes “Distinctive Nutritional Requirements” that they must be satisfied to meet the medical food definition.
Current dietary standards for setting nutrient requirements, dietary reference intakes and policy for food programs are based on population data, statistically evaluated to arrive at single-number recommendations, yet admitting to significant variability in individual values across the population. The patient with a disease or condition cannot legitimately be compared to the healthy general public. When more sensitive biomarkers of nutrient adequacy developed at the cell, tissue or organ level and validated, true “distinctive nutritional requirements” are likely to become identified for that individual and therefore, suitable for medical food or other “therapeutic nutrition” targeting those unique needs. Awareness of the importance of better characterizing nutritional status, taking into account the integrated systems approach of a holistic definition of “nutrition,” is growing among the nutritional science community. Influential organizations, such as NASEM are hosting workshops, engaging with thought leaders across multiple disciplines that collectively provide evidence-based evaluation of the published data. Financial backing for these workshops, from government agencies like FDA, NIH and patient groups, underscores the need for strong science to support a fair, effective and safety-oriented regulatory environment in which to accelerate commercializing true innovative nutritional solutions that benefit patients.
Timothy Morck, PhD, is president, Spectrum Nutrition LLC, providing expertise in scientific and regulatory areas in the food, pharmaceutical and medical fields. Drawing on 40 years of experience in clinical, academic, association and global industry executive positions, he brings a multidisciplinary perspective that integrates science and business objectives with a passion for personalized approaches to improving health. He is an active member of the American Society for Nutrition, Institute of Food Technologists, and The Obesity Society. He may be contacted at firstname.lastname@example.org.
Cite as: Morck T. “Opportunities and Challenges in New Nutritional Products Innovation. Do they fulfill regulatory criteria as medical foods?” Regulatory Focus. July 2018. Regulatory Affairs Professionals Society.