Regulation of Medical Foods

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.

-----------------------------------------------------------------------

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.

---------------------------------------------------------------------------

\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.

---------------------------------------------------------------------------

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;

---------------------------------------------------------------------------

\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.

---------------------------------------------------------------------------

(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\

--------------------------------------------------------------------------------------------------------------------------------------------------------

Disease state Patient population Product characteristics Examples of product claims

--------------------------------------------------------------------------------------------------------------------------------------------------------

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