[Federal Register Volume 61, Number 231 (Friday, November 29, 1996)]
[Proposed Rules]
[Pages 60661-60671]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-30441]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Ch. I.

[Docket No. 96N-0364]
RIN 0905-AD91


Regulation of Medical Foods

AGENCY: Food and Drug Administration, HHS.

ACTION: Advance notice of proposed rulemaking.

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SUMMARY: The Food and Drug Administration (FDA) is soliciting comments 
to initiate a reevaluation of its approach to the regulation of the 
broad group of heterogeneous products that are marketed as medical 
foods. FDA's goal is to arrive at a regulatory regime that will ensure 
that: These products are safe for their intended uses, especially 
because they are likely to be the sole or a major source of nutrients 
for sick and otherwise vulnerable people; claims for these products are 
truthful, not misleading, and supported by sound science; and the 
labeling of these products is adequate to inform consumers about how to 
use them in a safe and appropriate manner. The agency believes that 
there is a need to reevaluate its policy for regulating medical foods 
because of a number of developments, including enactment of a statutory 
definition of ``medical food,'' the rapid increase in the variety and 
number of products that are marketed as medical foods, safety problems

[[Page 60662]]

associated with the manufacture and quality control of these products, 
and the potential for fraud as claims that are not supported by sound 
science proliferate for these products.

DATES: Written comments by February 27, 1997.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857. Submit written requests for single copies of FDA's 
Compliance Program for Medical Foods (Compliance Program No. 7321.002) 
to the Freedom of Information Office (HFI-35), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857. Send two self-
addressed adhesive labels to assist that office in processing your 
requests.

FOR FURTHER INFORMATION CONTACT: Robert J. Moore, Center for Food 
Safety and Applied Nutrition (HFS-456), Food and Drug Administration, 
200 C St. SW., Washington, DC 20204, 202-205-4605.

SUPPLEMENTARY INFORMATION:

I. Background

    One of the first medical foods to be developed was the infant 
formula Lofenalac, a product that was designed for use in the 
dietary management of a rare genetic condition known as phenylketonuria 
(PKU). This product contains only a very limited amount of the 
essential amino acid phenylalanine because the individuals with this 
condition have an impaired ability to metabolize this amino acid. If 
infants with PKU consume foods that contain phenylalanine, harmful end 
products of phenylalanine metabolism accumulate in the body and can 
cause severe, irreversible mental retardation. Dietary management to 
carefully limit phenylalanine intake (for example, by using a formula 
that provides only a limited, minimal amount of this essential amino 
acid) can result in normal growth and development and avoid mental 
retardation.
    Before 1972, FDA regulated products like the infant formula 
Lofenalac as drugs under section 201(g)(1)(B) of the Federal 
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321(g)(1)(B)) because 
of their role in mitigating serious adverse effects of the underlying 
diseases. In 1972, FDA reassessed its position. At that time, such 
products were very limited in number and were being produced by a small 
number of reputable manufacturers with high standards of quality 
control. Additionally, the nutritional formulation requirements for 
this type of product were straightforward and well established by the 
medical community. FDA believed that the usefulness of these products 
in patient populations was widely accepted by health care 
professionals, and that close physician supervision ensured safe use in 
the patient population. The agency was interested in fostering 
innovation in the development of these products, most of which had been 
developed for the dietary management of diseases and conditions that 
are not widespread, to ensure that such products would be available at 
reasonable cost.
    For all these reasons, the agency concluded that a revision of its 
regulatory approach to these products was appropriate. At the same 
time, the agency recognized that use of these products for feeding 
healthy individuals could be hazardous. For example, an infant formula 
that was purposely formulated to be suitable for an infant with PKU 
would be nutritionally inadequate for a normal infant. Thus, the agency 
saw that it was important to differentiate these products from foods 
for general use. As a result, in 1972, FDA stated that the PKU product 
described above would no longer be regulated as a drug but rather as a 
``food for special dietary use'' \1\ (37 FR 18229 at 18230, September 
8, 1972). In addition, the agency began to follow a policy of 
regulating similar types of products as foods for special dietary use.
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    \1\ Although there was no statutory definition of a food for 
special dietary use in 1972, the term ``special dietary uses,'' as 
applied to food for humans, had been defined by regulation since 
1941. In the Federal Register of November 22, 1941 (6 FR 5921), FDA 
promulgated a regulation stating that the term ``special dietary 
uses'', as applied to food for man, means particular (as 
distinguished from general) uses of food, and that it means, among 
other things, ``uses for supplying particular dietary needs which 
exist by reason of a physical, physiological, pathological or other 
condition, including but not limited to the conditions of disease, 
convalescence, pregnancy, lactation, allergic hypersensitivity to 
food, underweight, and overweight.'' This part of the regulation 
remains unchanged in current Sec. 105.3(a)(1) (21 CFR 105.3(a)(1)).
    The statutory definition of ``special dietary use'' in section 
411(c)(3) of the act (21 U.S.C. 350(c)(3)) was added in 1976 (Pub. 
L. 94-278). It defines this term as a particular use for which a 
food purports or is represented to be used, including but not 
limited to the following:
    (A) Supplying a special dietary need that exists by reason of a 
physical, physiological, pathological, or other condition, including 
but not limited to the condition of disease, convalescence, 
pregnancy, lactation, infancy, allergic hypersensitivity to food, 
underweight, overweight, or the need to control intake of sodium.
    (B) Supplying a vitamin, mineral, or other ingredient for use by 
man to supplement his diet by increasing the total dietary intake.
    (C) Supplying a special dietary need by reason of being a food 
for use as the sole item of the diet.
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    Since 1972, the legislative and regulatory history of medical foods 
has reflected the agency's efforts to develop a regulatory framework to 
ensure the safety and nutritional adequacy of foods that are designed 
to meet distinctive nutritional requirements resulting from diseases or 
health conditions. Medical foods are used under the supervision of a 
physician when such distinctive nutritional requirements cannot be met 
with a conventional diet. These characteristics have led the agency to 
exempt medical foods from many of the requirements that apply to 
conventional foods.
    When FDA made nutrition labeling mandatory for certain foods in 
1973, the agency exempted certain types of foods for special dietary 
use from this requirement. In the preamble to the 1973 final rule on 
nutrition labeling (38 FR 2124 at 2126, January 19, 1973), FDA noted 
that nutrition labeling developed for foods intended for consumption by 
the general population was not well suited for some food products, 
including two types of foods for special dietary use: (1) Any food 
represented for use as the sole item of the diet; and (2) foods 
represented for use solely under medical supervision in the dietary 
management of specific diseases and disorders. Therefore, this final 
rule provided that these two types of foods for special dietary use 
would be exempt from the general requirements for nutrition labeling 
and were to be labeled in compliance with regulations that the agency 
intended to include in 21 CFR part 125 (later redesignated as 21 CFR 
part 105).
    The Orphan Drug Amendments of 1988 enacted, for the first time, a 
statutory definition of ``medical food'':

    The term ``medical food'' means 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.

(21 U.S.C. 360ee(b)(3))

Although Congress provided a statutory definition for medical foods, 
the legislative history of the Orphan Drug Amendments does not discuss 
the definition and, therefore, does not provide any further information 
regarding the types of products that the definition was intended to 
cover.
    In the Nutrition Labeling and Education Act of 1990 (the 1990 
amendments), Congress incorporated the definition of medical foods 
contained in the Orphan Drug Amendments of 1988 into section 
403(q)(5)(A)(iv) of the act (21 U.S.C. 343(q)(5)(A)(iv)) and exempted 
medical

[[Page 60663]]

foods from the nutrition labeling, health claim, and nutrient content 
claim requirements applicable to most other foods. In the Federal 
Register of November 27, 1991 (56 FR 60366 at 60377), FDA published a 
proposal to implement the mandatory nutrition labeling provisions of 
the 1990 amendments. The proposal discussed the statutory exemption for 
medical foods and advised that the agency considered the statutory 
definition of medical foods to ``narrowly constrain the types of 
products that can be considered to fall within this exemption.'' In the 
Federal Register of January 6, 1993, FDA published several final rules 
implementing the 1990 amendments. The final rule on mandatory nutrition 
labeling (58 FR 2079 at 2151, January 6, 1993) exempted medical foods 
from the nutrition labeling requirements and incorporated the statutory 
definition of a medical food into the agency's regulations at 
Sec. 101.9(j)(8) (21 CFR 101.9(j)(8)). In this regulation, FDA 
enumerated criteria that were intended to clarify the characteristics 
of medical foods. The regulation provides that a food may claim the 
exemption from nutrition labeling requirements only if it meets the 
following criteria in Sec. 101.9(j)(8):
    (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 \2\ nutrient needs that result from the 
specific disease or condition, as determined by medical evaluation;
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    \2\ The agency notes that experience has shown that the word 
that it should have used here is ``distinctive'' rather than 
``unique.'' Thus, in any rulemaking that results from the advance 
notice of proposed rulemaking, the agency will likely propose to 
amend Sec. 101.9(j)(8) accordingly.
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    (iv) It is intended to be used under medical supervision; and
    (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.

(58 FR 2079 at 2185)

    In the preamble to the final rule on mandatory nutrition labeling, 
FDA noted that it had received a number of comments asking for further 
clarification of the types of products that the agency considers to be 
medical foods. The agency acknowledged that such clarification would be 
helpful and announced that it intended to address the issue in the 
future (58 FR 2079 at 2151). In the same document, the agency also 
noted the need for labeling regulations for medical foods and 
reiterated its intention to propose such regulations.
    In 1990, the Life Sciences Research Office of the Federation of 
American Societies for Experimental Biology (LSRO/FASEB) published 
``Guidelines for the Scientific Review of Enteral Food Products for 
Special Medical Purposes'' (Ref. 1). This report defined medical foods 
as products that are distinct from foods for special dietary use in 
that they ``demonstrate greater suitability for nutritional management 
of a specific disease than standard enteral formulas'' and are intended 
for patients with ``special medically determined nutrient requirements, 
the dietary management of whom cannot be achieved by the modification 
of the normal diet alone, by other foods for special dietary uses, or 
by a combination thereof.'' The report proposed criteria that would 
establish a strict standard that a food would have to meet to be 
considered a medical food. LSRO/FASEB's proposed definition of a 
medical food did not include all foods that might be useful for persons 
with a disease or medical condition.

II. Reasons for Re-Evaluating Regulation of Medical Foods

A. Introduction

    The agency is re-evaluating its policy for regulating medical foods 
in light of several developments, including the enactment of a 
statutory definition of ``medical food,'' the impact of the 1990 
amendments, the rapid increase in the variety and number of products 
that are marketed as medical foods and in the uses for which these 
products are marketed, safety problems associated with the manufacture 
and quality control of these products, and the resulting potential for 
injury to consumers and fraud as claims that are not supported by sound 
science proliferate for these products.

B. The Definition of ``Medical Food'' and the Impact of the 1990 
Amendments: the Medical Foods Paradox

    The statutory definitions of ``medical food'' (21 U.S.C. 
360ee(b)(3)) and food for special dietary use (see section 411(c)(3) of 
the act), and the differing treatment of these two categories of 
products under the 1990 amendments to the act (i.e., medical foods are 
exempted under section 403(q)(5)(A)(iv) and (r)(5)(A) of the act, while 
there is no special treatment of foods for special dietary use), 
establish that Congress intended that medical foods and foods for 
special dietary use be viewed and regulated as separate and distinct 
categories of products. Foods for special dietary use are subject to 
the same nutrition labeling requirements and requirements for health 
claims and nutrient content claims established for most other foods by 
the 1990 amendments. Thus, foods for special dietary use, like ordinary 
foods, must be labeled with certain nutrition information in a 
prescribed format to ensure that such information is presented in an 
informative and understandable fashion. Moreover, any nutrient content 
claims or health claims on the label or in the labeling of a food for 
special dietary use must have been authorized by FDA to ensure that the 
claim is scientifically valid and is presented in such a way that it is 
truthful and not misleading.
    In contrast, under the 1990 amendments, medical foods are 
specifically exempted from the requirements for nutrition labeling, 
nutrient content claims, and health claims. Thus, a medical food that 
is intended for the specific dietary management of a disease or 
condition for which distinctive nutritional requirements have been 
established may be sold without any nutrition information on its label 
or labeling, and it may bear claims that have not been evaluated under 
the 1990 amendments to ensure that they are scientifically valid. 
Moreover, there is no assurance that the formulation of a medical food 
has been evaluated prior to sale to ensure that it is suitable for the 
intended patient population. The exemption from the requirements of the 
1990 amendments, therefore, creates a troubling paradox: Medical foods 
intended for use by sick people are subject to much less scrutiny than 
virtually all other foods, which are intended for the healthy general 
population. This lack of scrutiny creates a situation that could have 
adverse public health consequences if these

[[Page 60664]]

products bear claims that are not scientifically valid, or if their 
labeling does not disclose nutrition or other information that is 
necessary for the safe and effective use of the food.

C. Universe of Products

    The number and variety of products marketed as medical foods, the 
number and types of claims made for such products, the types of 
ingredients included in these products, and the number of manufacturers 
of these products have increased significantly since the mid-1970's. In 
1974, a limited survey of pharmaceutical and food manufacturers 
revealed that fewer than three dozen products were being sold as 
medical foods (Ref. 2). As of 1989, however, well over 200 products 
were being sold as medical foods (Ref. 3). Table 1 lists several types 
of products being marketed as medical foods with examples of claims 
being made by vendors of these products.
    However, many products marketed as medical foods may not qualify as 
such under the statutory definition of medical foods. Many of these 
products, for example, complete liquid nutrition products, are not 
formulated or promoted for the dietary management of a particular 
disease or condition but rather are formulated and marketed for use by 
the general population as supplements to a normal diet or as meal 
replacements.
    Enteral nutrition is nutrition provided through the 
gastrointestinal tract, taken by mouth or provided through a tube or 
catheter that delivers nutrients beyond the oral cavity (i.e., directly 
to the stomach or small intestine). This document uses the term 
``enteral nutrition products'' to refer to products that have been 
marketed as medical foods; ``statutory medical foods'' to refer to 
enteral nutrition products that meet the statutory definition of a 
medical food in section 5(b)(3) of the Orphan Drug Amendments (21 
U.S.C. 360ee(b)(3)); and ``nonstatutory enteral nutrition products'' to 
refer to enteral nutrition products that have been marketed as medical 
foods but that do not meet the statutory definition of a medical food.
    Enteral nutrition products labeled and marketed as medical foods 
are generally liquid or powdered products formulated to meet specific 
needs. They include nutritionally complete formulations, nutritionally 
incomplete formulations (such as modular products that contain only one 
nutrient or a small number of nutrients and that are intended for use 
with other formulations), formulations for metabolic disorders 
(including inborn errors of metabolism) in patients over 12 months of 
age, and oral rehydration products. While many such products are 
intended to provide a complete source of nutrition and are consumed 
orally or administered by feeding tube for this use, the labeling of 
such products frequently bears claims related to an intended use of the 
product in the management of a disease or condition, e.g., in 
alleviating specific symptoms and clinical manifestations of a 
particular disease.

 Table 1.--Examples of Currently Available Types of Enteral Nutrition Products for Use in Various Disease States and for Patients With Inborn Errors of 
                                                                     Metabolism \1\                                                                     
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              Disease state                          Patient population                    Product characteristics           Examples of product claims 
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Kidney (renal) disease (e.g., chronic or  Hospitalized patients (including         Type and quality of protein............  ``* * * complete balanced   
 acute kidney failure).                    critical care patients) and home care                                             nutrition for renal        
                                           patients.                                                                         patients * * * a moderate- 
                                                                                                                             protein, low-electrolyte,  
                                                                                                                             low-fluid, high-calorie    
                                                                                                                             formula * * * designed to  
                                                                                                                             provide balanced-nutrition 
                                                                                                                             for dialyzed patients with 
                                                                                                                             chronic or acute renal     
                                                                                                                             failure * * *''            
                                                                                                                            ``Under careful dietary     
                                                                                                                             management * * * can       
                                                                                                                             maintain uremic patients in
                                                                                                                             good nutritional status,   
                                                                                                                             promote anabolism and lower
                                                                                                                             and stabilize blood urea   
                                                                                                                             nitrogen levels * * *''    
Liver disease (e.g., coma or              Hospitalized patients (including         Type and quality of protein............  ``Provides adequate protein 
 encephalopathy associated with            critical care patients) and home care                                             without inducing or        
 hepatitis or cirrhosis).                  patients.                                                                         exacerbating hepatic       
                                                                                                                             encephalopathy''           
                                                                                                                            An aggressive nutritional   
                                                                                                                             regimen * * * may be useful
                                                                                                                             in the nutritional         
                                                                                                                             management of alcoholic    
                                                                                                                             liver-disease patients in  
                                                                                                                             reversing malnutrition,    
                                                                                                                             liver dysfunction, and     
                                                                                                                             encephalopathy.''          
Hypermetabolic states (e.g., severe       Hospitalized patients (including         Type and quality of protein; added       ``A nutritionally complete  
 burns, trauma or infection).              critical care patients).                 amino acids; elevated levels of          formula that provides a    
                                                                                    specific vitamins and/or minerals.       concentrated source of     
                                                                                                                             calories for patients with 
                                                                                                                             restricted fluid allowance 
                                                                                                                             or increased energy needs *
                                                                                                                             * * useful in the dietary  
                                                                                                                             management of volume-      
                                                                                                                             restricted patients,       
                                                                                                                             oncology patients,         
                                                                                                                             hypermetabolic conditions, 
                                                                                                                             trauma, sepsis, and post   
                                                                                                                             major surgery.''           
                                                                                                                            ``Specialized elemental     
                                                                                                                             nutrition with glutamine   
                                                                                                                             for metabolically stressed 
                                                                                                                             patients with impaired GI  
                                                                                                                             function * * * stimulates  
                                                                                                                             intestinal epithelial cell 
                                                                                                                             proliferation in injured   
                                                                                                                             rats * * * diminished      
                                                                                                                             mucosal atrophy associated 
                                                                                                                             with injury by stimulating 
                                                                                                                             intestinal cell            
                                                                                                                             replacement.''             
Lung disease (e.g., chronic obstructive   Hospitalized patients (including         High fat, low carbohydrate content.....  ``A nutritionally complete, 
 pulmonary disease, acute respiratory      critical care patients) and home care                                             ready-to-use formula * * * 
 distress syndrome, cystic fibrosis).      patients.                                                                         uniquely formulated to     
                                                                                                                             provide a diet high in     
                                                                                                                             nitrogen and restricted in 
                                                                                                                             carbohydrates to aid in the
                                                                                                                             control of metabolic       
                                                                                                                             alterations in * * *       
                                                                                                                             various stress states      
                                                                                                                             including respiratory      
                                                                                                                             insufficiency * * * CO2    
                                                                                                                             production is minimized    
                                                                                                                             while providing appropriate
                                                                                                                             nutrient levels.''         
                                                                                                                            ``Proven effective in the   
                                                                                                                             dietary management of      
                                                                                                                             patients with respiratory  
                                                                                                                             disease * * * reduced CO2  
                                                                                                                             production in chronic      
                                                                                                                             obstructive pulmonary      
                                                                                                                             disease and cystic fibrosis
                                                                                                                             patients.''                

[[Page 60665]]

                                                                                                                                                        
Compromised immune function.............  Hospitalized patients (including         Enriched with specific amino acids;      ``Specialized complete      
Human immunodeficiency virus (HIV)         critical care patients) and home care    fortified with increased levels of       nutrition to provide       
 infection, acquired immune deficiency     patients.                                vitamins.                                effective nutritional      
 syndrome (AIDS).                                                                                                            management for people with 
                                                                                                                             HIV infection or AIDS * * *
                                                                                                                             to support immune          
                                                                                                                             function.''                
                                                                                                                            ``Increases CD4/CD8 ratio,  
                                                                                                                             one aspect of immune system
                                                                                                                             * * * CD4/CD8 increased by 
                                                                                                                             day 5, indicating an       
                                                                                                                             improved T-helper cell     
                                                                                                                             function.''                
                                                                                                                            ``7 days of use helped      
                                                                                                                             support return of immune   
                                                                                                                             function to preoperative   
                                                                                                                             levels; 22 percent         
                                                                                                                             reduction in mean length of
                                                                                                                             hospital stay; 70 percent  
                                                                                                                             reduction in infections and
                                                                                                                             wound complications.''     
Diabetes mellitus.......................  Hospitalized patients (including         Type and quantity of carbohydrate; high  ``High fiber, low           
                                           critical care patients) and home care    fiber.                                   carbohydrate * * * for     
                                           patients.                                                                         patients with abnormal     
                                                                                                                             glucose tolerance * * * to 
                                                                                                                             enhance blood glucose      
                                                                                                                             control * * * in persons   
                                                                                                                             with type I or type II     
                                                                                                                             diabetes mellitus and      
                                                                                                                             stress-induced             
                                                                                                                             hyperglycemia.''           
Malabsorption, as found in: Inflammatory  Hospitalized patients (including         Pre-digested macronutrients; altered     ``A nutritionally complete  
 bowel disease (ulcerative colitis,        critical care patients) and home care    type or quantity of fat.                 enteral nutritional with * 
 Crohn's disease); radiation enteritis;    patients.                                                                         * * 85 percent of fat      
 short bowel syndrome.                                                                                                       derived from (medium chain 
                                                                                                                             triglyceride) (MCT) oil--a 
                                                                                                                             lipid clinically proven to 
                                                                                                                             result in less severity and
                                                                                                                             incidence of diarrhea and  
                                                                                                                             abdominal discomfort in    
                                                                                                                             individuals with fat       
                                                                                                                             malabsorption * * *        
                                                                                                                             resulting from conditions  
                                                                                                                             such as HIV infection,     
                                                                                                                             inflammatory bowel disease,
                                                                                                                             cystic fibrosis, or short  
                                                                                                                             bowel syndrome.''          
                                                                                                                            ``Comparision of a semi-    
                                                                                                                             elemental diet with        
                                                                                                                             Prednisolone in the primary
                                                                                                                             treatment of active ileal  
                                                                                                                             Crohn's disease * * * this 
                                                                                                                             new flavored semi-elemental
                                                                                                                             diet * * * may be as       
                                                                                                                             effective as steroids in   
                                                                                                                             inducing remission in ideal
                                                                                                                             Crohn's disease.''         
Oral rehydration solutions..............  Hospitalized patients (including         Solutions of water, electrolytes and a   ``To quickly restore fluids 
                                           critical care patients) and home care    carbohydrate source.                     and minerals lost in       
                                           patients.                                                                         diarrhea and vomiting in   
                                                                                                                             infants and children * * * 
                                                                                                                             for maintenance of water   
                                                                                                                             and electrolytes following 
                                                                                                                             corrective parenteral      
                                                                                                                             therapy for severe         
                                                                                                                             diarrhea.''                
                                                                                                                            ``Enteral rehydration       
                                                                                                                             solution * * * to prevent  
                                                                                                                             dehydration and to correct 
                                                                                                                             mild to moderate           
                                                                                                                             dehydration associated with
                                                                                                                             fluid and electrolyte      
                                                                                                                             loss.''                    
                                                                                                                            ``Pediatric electrolyte oral
                                                                                                                             maintenance solution * * * 
                                                                                                                             to restore body water and  
                                                                                                                             minerals lost in children's
                                                                                                                             diarrhea and vomiting * * *
                                                                                                                             prevents dehydration.''    
Phenylketonuria (PKU)...................  Patients with phenylketonuria..........  Restrict dietary phenylalanine.........  ``A phenylalanine-free food 
                                                                                                                             to aid in the nutritional  
                                                                                                                             management of              
                                                                                                                             hyperphenylalaninemia      
                                                                                                                             including PKU.''           
                                                                                                                            ``Phenylalanine-free to     
                                                                                                                             allow greater intake of    
                                                                                                                             complete protein.''        
                                                                                                                            ``Phenylalanine-free for    
                                                                                                                             pregnant women, women in   
                                                                                                                             the childbearing years and 
                                                                                                                             individuals over 8 years of
                                                                                                                             age.''                     
Maple syrup urine disease...............  Patients with maple syrup urine disease  Restrict dietary branched-chain amino    ``To be used only for the   
                                                                                    acids (isoleucine, leucine and valine).  dietary management of      
                                                                                                                             infants and children with  
                                                                                                                             maple syrup urine disease  
                                                                                                                             or other disorders of      
                                                                                                                             branched-chain amino acid  
                                                                                                                             metabolism under the direct
                                                                                                                             and continuing supervision 
                                                                                                                             of a physician.''          
                                                                                                                            ``A branched-chain amino    
                                                                                                                             acid-free medical food * * 
                                                                                                                             * for nutrition support of 
                                                                                                                             children and adults with   
                                                                                                                             branch-chain ketoaciduria  
                                                                                                                             (maple syrup urine         
                                                                                                                             disease).''                
                                                                                                                            ``Isoleucine-, leucine- and 
                                                                                                                             valine-free for individuals
                                                                                                                             over 8 years of age and    
                                                                                                                             women in the childbearing  
                                                                                                                             years.''                   
Hereditary tyrosinemia: Type I Type II..  Patients with hereditary tyrosinemia...  For Type I: Restrict dietary tyrosine,   ``A phenylalanine-, tyrosine-
                                                                                    phenylalanine and methionine;.            and methionine-free       
                                                                                   For Type II: Restrict dietary tyrosine    medical food * * * for     
                                                                                    and phenylalanine.                       nutrition support of       
                                                                                                                             infants and toddlers with  
                                                                                                                             tyrosinemia type I.''      
                                                                                                                            ``A special formula powder  
                                                                                                                             for use in the dietary     
                                                                                                                             management of hereditary   
                                                                                                                             tyrosinemia II * * * a     
                                                                                                                             phenylalanine- and tyrosine-
                                                                                                                             free medical food for      
                                                                                                                             nutrition support of       
                                                                                                                             children and adults with   
                                                                                                                             tyrosinemia type II.''     
                                                                                                                            ``A special formula powder  
                                                                                                                             for use in the dietary     
                                                                                                                             management of hereditary   
                                                                                                                             tyrosinemia II * * * very  
                                                                                                                             low in tyrosine and        
                                                                                                                             phenylalanine * * * ''     
Homocystinuria..........................  Patients with homocystinuria...........  Restrict dietary methionine............  ``A special diet powder     
                                                                                                                             without added methionine   
                                                                                                                             for dietary management of  
                                                                                                                             individuals with           
                                                                                                                             homocystinuria.''          
                                                                                                                            ``A methionine-free medical 
                                                                                                                             food * * * for nutritional 
                                                                                                                             support of children and    
                                                                                                                             adults with vitamin B6-    
                                                                                                                             nonresponsive              
                                                                                                                             homocystinuria or          
                                                                                                                             hypermethioninemia,''      

[[Page 60666]]

                                                                                                                                                        
                                                                                                                            ``Methionine-free for       
                                                                                                                             individuals over 8 years of
                                                                                                                             age and women in the       
                                                                                                                             childbearing years.''      
Urea cycle disorders (e.g., argininemia,  Patients with urea cycle disorders.....  Restrict dietary protein as tolerated    ``A non-essential amino acid-
 ornithine transcarbamylase deficiency,                                             without causing hyperammonemia.          free medical food * * * for
 methylmalonic aciduria).                                                                                                    nutrition support of       
                                                                                                                             children and adults with a 
                                                                                                                             defect in a urea cycle     
                                                                                                                             enzyme * * * ''            
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ This is a summary description of products available for dietary management of the listed diseases and inborn errors of metabolism. Some of these    
  diseases and conditions have many variations, each requiring distinctive dietary restrictions or supplements to the diet. A number of products are    
  available for several of the listed diseases and conditions, and the actual composition of these products may vary slightly from the product          
  characteristics given in this summary.                                                                                                                

D. Safety Problems

    As discussed above, there has been a dramatic increase over the 
past 20 years in the number and types of products that purport to be 
medical foods. The number of manufacturers producing these products has 
also increased. As the number of manufacturers has grown, the level of 
industry experience in the current good manufacturing practice (CGMP) 
and quality control procedures necessary to produce products that 
contain nutrients within a narrow range of declared label values has 
become quite variable. Medical foods are complex formulated products, 
generally requiring sophisticated and exacting technology comparable to 
that used in the manufacture of infant formulas and drugs. Moreover, 
the populations that consume these products, often as the sole or a 
major source of nutrition, are extremely vulnerable, e.g., pediatric 
patients in periods of growth and development, the elderly, patients 
who have serious illnesses, and patients in intensive care units. 
Although excessive or, conversely, insufficient amounts of particular 
nutrients may not be a health hazard when consumed by healthy persons, 
serious adverse consequences (even death) may result when these 
vulnerable populations consume these products for long, or even short, 
periods of time.
    Significantly, in recent years, FDA has become aware of some 
serious problems with foods that purport to be medical foods. In 1986, 
four infants died as a result of being fed an oral rehydration solution 
that contained lethal concentrations of potassium. FDA identified the 
oral rehydration solution as the cause of these deaths (Ref. 4), 
inspected the site where the product was manufactured, and analyzed the 
product's nutrient content. FDA determined that elevated amounts of 
potassium occurred in the product because CGMP had not been followed. 
Notably, weighing scales were used improperly, and persons responsible 
for the formulation of product lacked adequate training.
    Results of a compliance program that FDA initiated for medical 
foods in 1988, and followup on adverse reactions reported to the 
agency, have identified examples of deviations from CGMP that have 
caused the actual nutrient content of the product to deviate 
significantly from the declared label value. Some deviations have been 
significant enough to create acute, life-threatening health hazards and 
have led to product recalls. For example, in 1989, problems with a 
nutritionally complete product containing excessive amounts of 
potassium and sodium were brought to FDA's attention as a result of a 
complaint from the Veterans Administration Medical Center in Nashville, 
TN. Administration of this product to a patient resulted in 
hyperkalemia, or elevated blood potassium levels, which can have life-
threatening consequences, including fatal cardiac arrhythmias. This 
patient required intensive medical treatment to reduce blood potassium 
levels and to prevent the serious side effects of hyperkalemia. FDA 
inspection of the facility that had manufactured this product revealed 
serious flaws in CGMP. These flaws resulted in extreme variability in 
product composition between lots or individual packets of product, 
which became evident when the product was analyzed by FDA for nutrient 
composition. This product was recalled (Ref. 5).
    In 1993, in response to a complaint to FDA from a medical center in 
Seattle, WA, FDA analysis of a complete nutritional product being 
administered enterally to patients in an intensive care unit revealed 
that the product contained levels of potassium that were approximately 
twice the amount declared on the label. The agency concluded that this 
product represented an acute, potentially life-threatening hazard to 
persons with impaired kidney function, particularly those who were not 
being closely monitored for serum potassium levels. As a result, a 
number of products were recalled (Ref. 6).
    FDA is also aware of problems involving potential microbiological 
contamination of products that purport to be medical foods. For 
example, in 1993, a modular product containing protein and a modular 
product containing carbohydrate were recalled because they had been 
manufactured under conditions in which they may have become 
contaminated with Salmonella (Ref. 7).

E. Claims and the Potential for Economic Fraud

    FDA has not, to date, undertaken a comprehensive review of the 
claims being made for products that purport to be medical foods but 
rather has evaluated claims for a small number of these products on a 
case-by-case basis, applying the following general principles:
    1. A product marketed for use as a medical food in the dietary 
management of a disease or condition should have characteristics that 
are based on scientifically validated distinctive nutritional 
requirements of the disease or condition.
    2. There should be a scientific basis for the formulation of the 
product and the claims made for the product.
    3. There should be sound, scientifically defensible evidence that 
the product does what it claims to do.
    The agency is concerned that some of the claims made for products 
that purport to be medical foods are not based on sound science, and 
that consumers that use products that bear such claims, and health 
professionals that recommend the use of such products, are being misled 
regarding the value of these products. In addition to the health risks 
created by unsafe or ineffective medical foods, consumers and third-
party payers, such as insurance companies and government

[[Page 60667]]

health care agencies, suffer significant economic losses when products 
marketed as medical foods do not do what they claim to do.
    A number of publications by and for health care professionals 
express concern about unsupported claims for foods that purport to be 
medical foods. For example, a recent edition of a book published by the 
United States Pharmacopeial Convention, Inc., USP DI, Volume I, Drug 
Information for the Health Care Professional (Ref. 8), lists enteral 
nutrition products that are formulated to meet nutrient requirements 
for individuals with specific diseases but states: ``In general, 
scientific evidence for efficacy of these products is weak and requires 
further study.'' The 1990 LSRO/FASEB report ``Guidelines for the 
Scientific Review of Enteral Food Products for Special Medical 
Purposes'' (Ref. 1) noted that products containing substances such as 
essential amino acids, peptides, and medium-chain triglycerides were 
available, and that such products were represented as being useful for 
the dietary management of diseases and disorders. However, the report 
also stated that clinical trials of these preparations were limited, 
and that ``none has fully confirmed or refuted the putative advantages 
of these products over ordinary nutritionally adequate preparations.''

III. Clarification of the Medical Food Definition

    In the preamble to one of the proposed rules implementing the 1990 
amendments, FDA advised that it considered the statutory medical food 
definition to narrowly constrain the types of products that can be 
considered to be medical foods (56 FR 60366 at 60377). As noted 
previously in this document, however, the agency recognizes that the 
universe of products that purport to be medical foods has expanded 
beyond the statutory definition of a medical food to include foods that 
are more appropriately foods for special dietary use. In part, this 
expansion has occurred because many have difficulty distinguishing 
between medical foods and foods for special dietary use. While the 
agency recognizes that some ambiguity exists in the distinction between 
these two types of foods, the statutory language provides several bases 
on which to distinguish medical foods from foods for special dietary 
use.

A. ``Distinctive Nutritional Requirements''

    A fundamental element of the medical food definition that 
distinguishes this type of product from a food for special dietary use 
is the statutory requirement that a medical food be intended to meet 
distinctive nutritional requirements of a disease or condition. Under 
21 U.S.C. 360ee(b)(3), distinctive nutritional requirements must be 
based on recognized scientific principles and established by medical 
evaluation. The law does not define what constitutes a ``distinctive 
nutritional requirement,'' however, and there is more than one possible 
interpretation. FDA welcomes public comment on what definition of 
``distinctive nutritional requirement'' will best protect and promote 
the public health. The agency is suggesting two possible 
interpretations of this phase.
1. Physiological Interpretation of ``Distinctive Nutritional 
Requirement''
    ``Distinctive nutritional requirement'' may be interpreted to refer 
to the body's requirement for specific amounts of nutrients to maintain 
homeostasis (the state of equilibrium in the body with respect to 
various functions and to the chemical compositions of the fluids and 
tissues) and sustain life; that is, the amount of each nutrient that 
must be available for use in the metabolic and physiological processes 
necessary to sustain life.
    The nutritional requirements of healthy people for specific 
nutrients reflect their quantitative and qualitative requirements for 
absorbed nutrients (i.e., the physiological requirement for the 
nutrient), with adjustments for common inefficiencies associated with 
absorption, metabolism, and retention. However, the dietary management 
of patients with specific diseases requires, in some instances, the 
ability to meet nutritional requirements that differ substantially from 
the needs of healthy persons. For example, in establishing the 
recommended dietary allowances for the general, healthy population, the 
Food and Nutrition Board of the Institute of Medicine, National Academy 
of Sciences recognized that different or distinctive physiologic 
requirements may exist for certain persons with ``special nutritional 
needs arising from metabolic disorders, chronic diseases, injuries, 
premature birth, other medical conditions, and drug therapies'' (Ref. 
9). Thus, the distinctive nutritional needs associated with a disease 
reflect the total amount needed by a healthy person to support life or 
maintain homeostasis, adjusted for the distinctive changes in the 
nutritional needs of the patient as a result of the effects of the 
disease process on absorption, metabolism, and excretion. These 
distinctive nutritional requirements may be greater than, less than, or 
in a narrower range of tolerance than for an otherwise healthy 
individual.
    Under this physiological interpretation of ``distinctive 
nutritional requirements, ``medical foods'' are foods that are 
formulated to aid in the dietary management of a specific disease or 
health-related condition that causes distinctive nutritional 
requirements that are different from the nutritional requirements of 
healthy people. Foods for special dietary use, on the other hand, are 
foods that are specially formulated to meet a special dietary need, 
such as a food allergy or difficulty in swallowing, but that provide 
nutrients intended to meet ordinary nutritional requirements. The 
special dietary needs addressed by these foods do not reflect a 
nutritional problem per se; that is, the physiological requirements for 
nutrients necessary to maintain life or homeostasis addressed by foods 
for special dietary use are the same as those of normal, healthy 
persons. These foods are formulated in such a way that only the 
ingredients or physical form of the diet is different. For example, a 
person who has difficulty swallowing solid food may have a special 
dietary need for a food that is in liquid form, but this special 
dietary need does not change his or her physiologic nutrient 
requirements. Similarly, a person who is allergic to specific food 
proteins (e.g., gluten) may need foods specially formulated not to 
contain these proteins. However, the specially formulated food still 
would provide the same amount of protein (i.e., amino acids) as is 
needed by the general population because the quantitative and 
qualitative amount of protein required by the body is similar in both 
healthy and protein-sensitive patients. Thus, foods for special dietary 
use are foods that are intended to meet ordinary nutritional 
requirements through special dietary means.
2. Alternative Interpretation of ``Distinctive Nutritional 
Requirement''
    ``Distinctive nutritional requirement'' may also be interpreted to 
encompass physical or physiological limitations in a person's ability 
to ingest or digest conventional foods, as well as distinctive 
physiological nutrient requirements. The FASEB report on medical foods 
stated that medical foods are for ``patients with limited or impaired 
capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs 
or certain nutrients contained therein, or (who) have other special 
medically determined nutrient requirements'' (Ref. 1). This definition 
would include uses that a purely

[[Page 60668]]

physiological definition of ``distinctive nutritional requirements'' 
would exclude, such as foods intended for persons not able to ingest 
foods in certain physical forms (e.g., solid food), foods intended for 
persons who need a concentrated form of nutrition because of reduced 
appetite as a result of disease or convalescence), or foods intended 
for persons who may have other physical limitations on the amount or 
composition of food that they can consume. Although these types of 
conditions do not necessarily result in nutrient needs different from 
those of healthy persons, they represent a situation where it may be 
necessary that the food be formulated and manufactured within very 
narrow tolerances to ensure that the food provides most or all of the 
essential nutrients, as the persons for whom the food is intended may 
not be able to eat a variety of foods to ensure that they meet their 
nutrient requirements.
    Therefore, it may be appropriate to define ``distinctive 
nutritional requirements'' to include those requirements that result 
from a disease or condition that cause a physical or physiological 
limitation in the ability of a person to ingest or digest conventional 
nutrient sources and result in that person needing specially formulated 
foods to meet part or all of their daily nutrient needs. Defining this 
term in this way may be appropriate because these circumstances create 
nutritional needs that are more narrowly defined than those of healthy 
persons, because the patient is relying on only a limited number of 
foods or a single food for sustenance. The agency asks for comments on 
whether persons with an impaired ability to ingest or digest specific 
foods because of a disease or condition, or who have physical or 
physiological limitations that cause them to rely on an enteral 
nutrition product for a significant part or all of their nutrient 
needs, have ``distinctive nutritional requirements'' within the meaning 
of the medical food definition.

B. ``Under the Supervision of a Physician''

    The second element of the medical food definition that 
distinguishes a medical food from a food for special dietary use is the 
statutory requirement that a medical food be ``formulated to be 
consumed or administered enterally under the supervision of a 
physician.'' As stated in the preamble to the proposed rule 
implementing the nutrition labeling requirements of the 1990 amendments 
(56 FR 60366 at 60377), ``under the supervision of a physician'' means 
that the intended use of a medical food is for the dietary management 
of a patient receiving active and ongoing medical supervision (e.g., in 
a health care facility or as an outpatient). The physician determines 
that the medical food is necessary to the patient's overall medical 
care, and the patient consults the physician on a recurring basis.
    Medical foods are intended for the dietary management of patients 
who have a short-term or long-term medical need for a particular 
nutrient or combination of nutrients to meet distinctive nutritional 
requirements. The use of a medical food requires ongoing physician 
oversight to ensure that the food effectively meets the distinctive 
nutritional requirements of the patient's disease or condition, and 
that the use of an enteral medical food is the appropriate means (i.e., 
as opposed to a patient requiring a parenteral nutrition product) to 
meet the patient's distinctive nutritional requirements. Therefore, 
medical foods are foods that are an integral component of the clinical 
management of a patient. Medical foods are not foods simply recommended 
by a physician as part of an overall diet designed to reduce the risk 
of a disease or medical condition, to lose or maintain weight, or to 
ensure the consumption of a healthy diet. Foods recommended by a 
physician for these purposes may be foods for special dietary use, but 
they are not medical foods.

C. ``Specific Dietary Management''

    The third fundamental element of the definition of a medical food 
that distinguishes a medical food from a food for special dietary use 
is the statutory requirement that a medical food be intended for the 
specific dietary management of a disease or condition. The term 
``specific dietary management'' in the statutory definition of medical 
foods evidences that Congress intended these foods to be an integral 
part of the clinical treatment of patients. Consistent with this 
interpretation of this term, the LSRO/FASEB Panel concluded that the 
objectives of incorporating the use of medical foods into patient 
management were, in part, to ``ameliorate clinical manifestations of 
the disease,'' ``favorably influence the disease process,'' and 
``positively influence morbidity and mortality (patient outcomes)'' 
(Ref. 1). There is no language corresponding to ``specific dietary 
management'' in the statutory definition applicable to foods for 
special dietary use. Thus, although they may be useful in supplying the 
special dietary needs of patients who have a disease or other condition 
that prevents them from eating normally, foods for special dietary use, 
unlike medical foods, are not specifically tailored for use as the 
nutritional component of the patient's treatment.

D. Summary

    The statutory definitions of medical foods and foods for special 
dietary use overlap to the extent that both categories encompass foods 
that are intended for use by sick people. The differences in the 
statutory definitions evidence, however, that Congress intended foods 
for special dietary use under section 411(c)(3)(A) of the act to be a 
broader category of foods for use by people with special dietary needs 
or desires, while it intended medical foods to be a narrower category 
of foods for use by people with particular diseases or conditions that 
have distinctive nutritional requirements. Since a medical food must 
address the ``distinctive nutritional requirements'' of a disease or 
condition, a medical food is suitable only for use by patients with 
that disease or condition. Of course, it is possible for more than one 
disease or condition to create the same distinctive nutritional 
requirements. A product that is intended to address the distinctive 
nutritional requirements of a particular disease is a medical food, 
even though some of those requirements may also be created by other 
diseases. A product that is designed to address a problem that is 
common to several diseases, but not the full range of requirements of 
any specific disease, would be a food for special dietary use. For 
example, the distinctive nutritional requirements of burn patients 
include a greater energy requirement due to hypermetabolism and a 
requirement for dietary glutamine because endogenous synthesis of this 
amino acid does not meet the metabolic requirement. Thus, a product 
formulated to meet the higher energy requirement due to the 
hypermetabolic state, but which does not meet the requirement for 
glutamine, would be a food for special dietary use and not a medical 
food because it does not meet the full range of distinctive nutritional 
requirements in patients with burn injuries.

IV. Need for Substantiation of Nutritional Efficacy and Claims Made in 
Product Labeling

    Because of their intended use in supplying the distinctive 
nutritional needs of patients who are ill or otherwise medically 
vulnerable, it is essential that medical foods be appropriately 
formulated for the particular disease or condition for

[[Page 60669]]

which they are labeled. Moreover, because the statutory definition of a 
medical food provides that these foods are part of the clinical 
management of a disease or condition, the definition necessarily 
incorporates a requirement that the product actually meet the 
distinctive nutritional requirements for the disease or condition. It 
is not enough that a manufacturer merely declare or subjectively intend 
that the product be used for the dietary management of patients with 
certain diseases or conditions. If the product, as formulated and 
consumed, does not actually meet those distinctive requirements, it 
would violate the act. Under any other view, the medical foods category 
would merely create a safe harbor for fraudulent claims targeted at 
those who are most vulnerable.
    Other elements of the statutory definition support this view. In 
defining the term ``medical food'' in the Orphan Drug Amendments, 
Congress included the requirement that distinctive nutritional 
requirements of a disease or condition exist, and that they be based on 
recognized scientific principles and established by medical evaluation. 
Thus, Congress established a strict standard for when a food qualifies 
as a medical food. The establishment of this strict standard for 
distinctive nutritional requirements necessarily implies an expectation 
that this standard will in fact be met.
    Acceptance of the manufacturer's intent that the product meets the 
special needs of the disease, without objective information to support 
the manufacturer's intent, would establish a subjective standard that 
would provide no assurance that the statutory standard has been met. 
Moreover, such a standard would ignore the fundamental differences 
between a medical food and other types of food. As stated above, a 
medical food is intended for use as the source of nutrients that are 
necessary in the medical management of a particular disease or 
condition. Thus, it is crucial to the health of the patient. No other 
type of food, including food for special dietary use, has such a direct 
relationship to the health of an individual. It is therefore necessary 
that the physician be able to rely on the medical food to effectively 
meet the distinctive nutritional requirements of the patient.
    Finally, the statutory scheme for regulation of claims relating to 
health and disease confirms the appropriateness of a strong standard 
for substantiation of the nutritional efficacy of medical foods. The 
act establishes a range of circumstances under which claims relating to 
health and disease may be made. At one end of the spectrum are 
conventional foods, which under section 403(r) of the act may bear a 
health claim only if FDA determines:

based on the totality of publicly available scientific 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.

At the other end of the spectrum are drugs, whose effectiveness in 
diagnosing, curing, mitigating, treating, or preventing disease must be 
established by substantial evidence, defined as:

evidence consisting of adequate and well-controlled investigations, 
including clinical investigations, by experts qualified by 
scientific training and experience to evaluate the effectiveness of 
the drug involved, on the basis of which it could fairly and 
responsibly be concluded by such experts that the drug will have the 
effect it purports or is represented to have under the conditions of 
use prescribed, recommended, or suggested in the labeling or 
proposed labeling thereof.

(Section 505(d)(7) of the act (21 U.S.C. 355(d)(7)).)

Clearly, medical foods fall somewhere between these two points, and the 
statutory scheme therefore requires some level of substantiation for a 
medical food's claimed usefulness in the dietary management of disease.
    When Congress enacted authorization for health claims on 
conventional foods, it provided that such claims would be permitted 
only if FDA determined that the substance-disease relationship that is 
the subject of the claim is supported by significant scientific 
agreement among experts. The House Report for the 1990 Amendments 
states: ``The standard is intended to be a strong one. The bill 
requires that the Secretary have a high level of confidence that the 
claim is valid'' (Ref. 10). The establishment of a ``strong'' 
scientific standard was necessary to ensure that claims were supported 
by adequate scientific evidence so that they would not be misleading, 
and so that consumers could have confidence in the scientific validity 
of the claimed substance-disease relationship. Thus, even a health 
claim for a food intended to be used by healthy individuals must meet a 
high standard.
    The reasons for requiring a strong standard of substantiation apply 
with even more force to medical foods. The statutory definition of a 
medical food states that such a food must be 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. As discussed earlier, this 
aspect of the definition makes it clear that Congress intended that 
claims made for medical foods be supported by scientific evidence, and 
it also constitutes a scientific standard that must be met for a food 
to be a medical food. The nature of these products (i.e., their 
intended use in the nutritional management of people affected by a 
disease or other condition) and the exemptions (i.e., from health claim 
requirements applicable to conventional foods) provided for them by 
virtue of their status as medical foods necessitate at least as much 
substantiation to support claims made for medical foods as for health 
claims on conventional foods. It would make no sense to establish a 
standard for claims on medical foods that was lower than the standard 
for health claims that are made for foods sold to healthy people.
    The agency is concerned that many claims made for products marketed 
as medical foods are not supported by adequate scientific evidence, and 
that these unsupported claims result in the inappropriate use of some 
products by patients and physicians when effective alternative 
nutritional strategies for managing the disease are available. One 
medical expert on enteral nutrition formulas voiced this concern by 
stating that since the:

introduction of nutritional support * * * as a specific therapeutic 
entity in the 1960's, a number of claims have been made, and widely 
believed, regarding its ability to improve the natural history of 
many diseases. However, these claims have been disseminated in the 
absence of supportive data from prospective randomized controlled 
trials * * *; in fact, when such studies have been performed, they 
have by and large not been able to demonstrate that [nutritional 
support] does improve morbidity and/or mortality.

(Ref. 11)

    A physician relies on the claims made for medical foods on their 
labels and in their labeling as a significant factor in deciding 
whether to use a particular medical food in the clinical management of 
a patient. Thus, it is essential that the claims made for such a 
product present an accurate interpretation of the scientific evidence 
concerning the usefulness of that product or specific formulation. It 
is critical for the safe and appropriate use of the medical food that 
the claims made for it are accurate and unbiased, and that they are 
based on a critical

[[Page 60670]]

evaluation of the science available to the manufacturer. The need for 
physicians and patients to have confidence that any claim that a 
product is a medical food formulated for the specific dietary 
management of a disease or condition requires that a strong standard of 
substantiation be in place. A strong standard of substantiation would 
be one that requires that all pertinent data be considered in the 
formulation of the product and in the development of any claims about 
its use.
    Further, the misbranding provisions of the act do not permit a 
food, including a medical food, to bear misleading labeling claims 
(section 403(a) of the act). Claims may be misleading not only because 
of affirmative representations made in the labeling, but also because 
the labeling fails to reveal facts material in the light of such 
representations with respect to consequences which may result from the 
use of the food under the conditions of use prescribed in the labeling 
or under usual or customary conditions of use (section 201(n) of the 
act). Thus, a medical food that bears claims that are not based on all 
the information available, and that do not permit the consumer or 
physician to make an informed choice, may be misbranded.
    In summary, the intended uses of medical foods, the statutory 
definition of a medical food, and the statutory scheme for regulating 
health and disease claims all point to the need for a strong standard 
of scientific evidence for the composition and effectiveness of medical 
foods to provide assurance to health care providers and patients of the 
nutritional utility of these products. The standard should be no less 
demanding than for health claims for foods intended for the healthy 
general population. Moreover, because medical foods are intended for 
use in the clinical management of seriously ill and injured patients, 
it may be appropriate and necessary to apply a more stringent standard 
to the scientific evidence used to support claims made for medical 
foods. The agency's preliminary view is that the scientific standard 
contained in the statutory medical food definition may require some of 
the same types of data for medical foods as are needed to support drug 
claims (e.g., data from clinical investigations). The agency asks for 
comments regarding how stringent a scientific standard is necessary to 
ensure the safe and appropriate use of a medical food for a particular 
disease or condition.

V. Agency Plans

    The agency is soliciting comments to initiate a reevaluation of its 
approach to the regulation of the broad group of heterogenous products 
marketed as medical foods and whether this approach serves the best 
interests of the consumers of such products. If the current regulatory 
approach is not adequate, the agency is interested in how it can 
improve the regulatory regime for medical foods to best serve those 
interests. FDA will review and consider all comments received. While 
this reevaluation is ongoing, however, the agency advises that it 
intends to continue to take regulatory action when necessary to protect 
consumers from unsafe or fraudulent products marketed as medical foods.

VI. Economic Issues

    Under Executive Order 12866, FDA will be required to consider the 
costs and benefits of any proposed regulations pertaining to medical 
foods when regulations are proposed. In addition, under the Regulatory 
Flexibility Act and the Small Business Regulatory Enforcement and 
Fairness Act, FDA will be required to consider the impacts on small 
entities of any such regulations.
    The primary benefit of any proposed change in the requirements 
applicable to medical foods will be a reduction in the health risks 
posed by medical foods that meet existing requirements. In addition, 
changes in the requirements applicable to medical foods that specify 
the level of scientific support required to make claims concerning the 
product will mean that consumers will have assurance that the claims 
are valid, and that the claims that are made provide reliable 
information. Other benefits will derive from the elimination of 
fraudulent and unsupported claims which will save consumers and third-
party payers money and will improve patient health because people will 
use products that are appropriate for their conditions instead of 
relying on those bearing unsupported claims that do not have a positive 
impact on their conditions.
    FDA asks for comments and information on the current health risks 
posed by medical foods meeting existing CGMP, labeling, and other 
applicable regulations. FDA also asks for comments on the degree to 
which these health risks may be reduced by additional regulation of 
medical foods, such as quality control requirements and additional CGMP 
and labeling regulations.
    The primary cost of any proposed change will be the difference 
between the current cost of producing and marketing medical foods and 
the anticipated cost of producing and marketing medical foods under the 
proposed change. For example, relevant costs may include the cost of 
changing labels, generating particular types of information for labels, 
changing production methods or facilities to accommodate new CGMP 
requirements, the generation of additional information to establish 
product safety and effectiveness, and the cost of any uncertainty or 
delays associated with a potential premarket notification process.
    FDA asks for comments on the costs that would be generated if 
medical foods were subject to additional regulatory requirements, such 
as quality control requirements, specific CGMP requirements, and 
labeling regulations. FDA also asks for comments on the impacts on 
small entities that would result if medical foods were subject to 
additional regulatory requirements of the type discussed in this 
document.

VII. Summary

    Patients rely on medical foods to meet the distinctive nutritional 
needs resulting from their disease or condition, and, therefore, 
medical foods are often a significant part of the clinical management 
of these patients. Despite the importance of medical foods, however, 
existing regulations do not provide clear guidance on what products 
should be considered to be medical foods or on requirements to ensure 
that these foods do what they purport to do and are safe for their 
intended use. There is no regulatory framework that establishes 
specific quality assurance requirements, ensures the safety of medical 
foods under their intended conditions of use, ensures that they provide 
the nutrients that they claim to provide within safe ranges, or ensures 
that the benefits claimed for their purported use are supported by 
adequate scientific evidence. Therefore, the agency asks for comments 
on the following questions:
    1. Is FDA's current approach to the regulation of medical foods 
adequate to ensure that food products claimed to be medical foods are 
safe and that the claims that they bear are valid? Is there a need for 
FDA to change its approach to the regulation of medical foods to better 
serve the needs of the patient populations that consume such products, 
and if so, what should the regulatory regime for medical foods be?
    2. What factors should FDA consider applying as criteria to 
determine what products meet the statutory definition of a medical 
food? Should the agency apply a physiological interpretation of 
``distinctive nutritional requirements'' in determining whether a 
product is a medical food, or should medical foods also include 
products that are used for

[[Page 60671]]

patients with ingestion or digestion problems but with otherwise 
``normal'' nutrient requirements? Would the latter interpretation be 
consistent with the act?
    3. What requirements are necessary to ensure the safe and 
appropriate use of: (a) Products that meet the statutory definition of 
a medical food? (b) products that have been marketed as medical foods 
but that do not meet the statutory definition of a medical food?
    Examples might include requirements that address product 
composition, current good manufacturing practice and quality control 
procedures, labeling requirements, and standards governing claims about 
the product and for foods that may be used as a sole item of the diet.
    4. To ensure the safety and effectiveness of a medical food, should 
the agency require that the manufacturer notify FDA before marketing 
the product, and that it submit evidence that establishes that the 
product will be safe for its intended use and that any claims made for 
the product are supported by sound science? What information should be 
included in such a submission?
    5. What standard should be used to determine the safety of a 
medical food?
    6. What quantity and quality of scientific evidence should be 
required to establish that a disease or condition has distinctive 
nutritional requirements based on recognized scientific principles?
    7. What quantity and quality of scientific evidence should be 
required to support the validity of claims made for medical foods?
    8. What information should be included on the label of a medical 
food or otherwise disclosed to health care professionals and consumers? 
Should the amount and detail of the information to be disclosed depend 
on the types of claims made for the medical food or on other 
characteristics of the product? What methods would be most effective in 
communicating information on the intended uses, benefits, and other 
characteristics of a medical food to enable physicians and consumers to 
make informed decisions regarding its use (e.g., labels, package 
inserts, detailed summaries of the science upon which a firm is basing 
the claims made for its product)?
    9. Should the agency develop regulations specifying quality control 
standards and procedures and current good manufacturing practice 
requirements for medical foods? What types of requirements are 
necessary (e.g., expiration dating, analysis of nutrient content, 
microbiological safety measurements, etc.)?
    10. How should FDA monitor the safety and effectiveness of medical 
foods already on the market? What elements are necessary components of 
an effective postmarket surveillance system for these products? Should 
a postmarket surveillance system for medical foods include requirements 
and procedures for the collection and reporting to FDA of safety- and 
efficacy-related product defects, adverse reaction reports, and 
complaints by health care professionals and consumers? Should 
manufacturers be required to collect information describing the 
outcomes associated with the use of medical food products in designated 
patient categories that would be available to FDA, health care 
providers, and consumers?

VIII. Comments

    Interested persons may, on or before February 27, 1997, submit to 
the Dockets Management Branch (address above) written comments 
regarding this proposal. Two copies of any comments are to be 
submitted, except that individuals may submit one copy. Comments are to 
be identified with the docket number found in brackets in the heading 
of this document. Received comments may be seen in the office above 
between 9 a.m. and 4 p.m., Monday through Friday.

IX. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.

    1. Talbot, J. M., ``Guidelines for the Scientific Review of 
Enteral Food Products for Special Medical Purposes,'' prepared for 
the Food and Drug Administration under FDA Contract No. 223-88-2124 
by the Life Sciences Research Office, Federation of American 
Societies for Experimental Biology, Bethesda, MD, 1990.
    2. Fisher, K. D., J. M. Talbot, and C. J. Carr, ``A Review of 
Foods for Medical Purposes: Specially Formulated Products for 
Nutritional Management of Medical Conditions,'' prepared for the 
Food and Drug Administration under Contract No. FDA 223-75-2090 by 
the Life Sciences Research Office, Federation of American Societies 
for Experimental Biology, Bethesda, MD, 1977.
    3. Hattan, D. G., and D. R. Mackey, ``A Review of Medical Foods: 
Enterally Administered Formulations Used in the Treatment of 
Diseases and Disorders,'' Food Drug Cosmetic Law Journal, 44:479-
502, 1989.
    4. Health Hazard Evaluation No. 1470, Food and Drug 
Administration, Center for Food Safety and Applied Nutrition, 200 C 
St. SW., Washington, DC, April 25, 1986.
    5. FDA Enforcement Report, August 23, 1989, Rockville, MD.
    6. FDA Enforcement Report, May 19, 1993, Rockville, MD.
    7. FDA Enforcement Report, July 28, 1993, Rockville, MD.
    8. The United States Pharmacopeial Convention, Inc., USP DI, 
Drug Information for the Health Care Professional, Volume I, Rand 
McNally, Taunton, MS, 1996.
    9. Subcommittee on the Tenth Edition of the RDA's, Food and 
Nutrition Board, Commission on Life Sciences, National Research 
Council, ``Recommended Dietary Allowances, 10th ed.,'' National 
Academy Press, Washington, DC, 1989.
    10. H. Rept. 101-538, 101st Cong., 2d sess., 19, ``Nutrition 
Labeling and Education Act of 1990,'' June 13, 1990.
    11. Koretz, R. L., A Critical Look at the Trials, Symposium #2, 
Immunonutrition in the ICU, In: Proceedings of the 19th Clinical 
Congress, American Society for Parenteral and Enteral Nutrition, 
Miami, FL, pp. 97-103, 1995.

    This document is issued under sections 4, 5, and 6 of the Fair 
Packaging and Labeling Act (15 U.S.C. 1453, 1454, 1455); sections 201, 
301, 402, 403, 404, 405, 409, 411, 412, 501, 502, 503, 505, and 701 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 342, 343, 
344, 345, 348, 350, 350a, 351, 352, 353, 355, 371); and 21 U.S.C. 
360ee(b)(3) (section 5(b)(3) of the Orphan Drug Amendments of 1988, as 
amended by Pub. L. 100-290).

    Dated: October 31, 1996.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 96-30441 Filed 11-27-96; 8:45 am]
BILLING CODE 4160-01-P