|Home | About | Journals | Submit | Contact Us | Français|
Medical foods and dietary supplements are used to treat rare inborn errors of metabolism (IEM) identified through state-based universal newborn screening. These products are regulated under Food and Drug Administration (FDA) food and dietary supplement statutes. The lack of harmony in terminology used to refer to medical foods and dietary supplements and the misuse of words that imply that FDA regulates these products as drugs have led to confusion. These products are expensive and, although they are used for medical treatment of IEM, third-party payer coverage of these products is inconsistent across the United States. Clinicians and families report termination of coverage in late adolescence, failure to cover treatment during pregnancy, coverage for select conditions only, or no coverage. We describe the indications for specific nutritional treatment products for IEM and their regulation, availability, and categorization. We conclude with a discussion of the problems that have contributed to the paradox of identifying individuals with IEM through newborn screening but not guaranteeing that they receive optimal treatment. Throughout the paper, we use the nutritional treatment of phenylketonuria as an example of IEM treatment.
Inborn errors of metabolism (IEM) include inherited biochemical disorders in which a specific enzyme defect interfers with the normal metabolism of protein, fat, or carbohydrate. As a result of diminished or absent enzyme activity in these disorders, certain compounds accumulate in the body to toxic levels and the levels of others that the body normally makes may become deficient. If they are not treated, these metabolic disturbances can lead to a host of medical and developmental consequences ranging from intellectual disability to severe cognitive impairment and even death. Through early identification and initiation of treatment, many of the adverse outcomes of IEM can be mitigated or prevented. For many IEM, treatment strategies rely on the provision of specialized medical foods and dietary supplements .
State-based universal newborn screening, one of the most successful preventive public health programs in the United States , identifies infants affected by IEM. See Table 1 for the Recommended Uniform Screening Panel that the Secretary of Health and Human Services (HHS) recommends for newborn screening. Not all of the disorders identified through newborn screening require treatment with medical foods, dietary supplements, or both. This paper focuses on IEM for which nutritional treatments serve as a primary therapy.
The Patient Protection and Affordable Care Act requires health care plans to provide coverage without cost sharing for newborn screening services, but no national policy calls for coverage of the costs of treatments. Some U.S. states pay for and provide medical foods as a part of their newborn screening program. Some other states that do not provide medical foods directly have enacted legislation that requires insurers to cover the costs of medical foods . However, policies regarding coverage vary from state to state and even in states that require coverage, some exceptions and exclusions exist, such as the Employee Retirement Income Security Act exemptions to legislative mandates.
In this paper, we describe the indications for specific nutritional treatment products for IEM and discuss the regulation, availability, and categorization of these products. Throughout the paper, we use the nutritional treatment of phenylketonuria (PKU) as an example of IEM treatment.
PKU is one of a class of hyperphenylalaninemia and is the most common IEM requiring nutritional treatment. It was the first disorder to be included in state-based newborn screening programs. PKU is an autosomal recessive disorder caused by insufficient or absent phenylalanine hydroxylase, the enzyme that converts the amino acid phenylalanine (Phe) to tyrosine (Tyr). Phe builds up in the blood and brain and Tyr becomes deficient. These metabolic abnormalities lead to toxic levels of brain Phe; inadequate neurotransmitter synthesis; intellectual disability; and abnormal motor, neurocognitive, and behavioral outcomes.
The incidence of PKU in the United States is between 1 in 13,500 and 1 in 19,000 [4, 5]. Currently, an estimated 300 of the 4.2 million babies born annually in the United States are diagnosed with PKU. Over 20 years, the total number of individuals living with PKU in the United States would be about 6,000.
Nutritional treatment for PKU was first used successfully in 1951, prior to the implementation of state public-health newborn screening programs (http://www.youtube.com/watch?v=OqZ7QHO5_hs). Since that time, nutritional treatment for PKU has been refined and is the mainstay of treatment for PKU . When initiated within the first weeks of life and maintained throughout life, an appropriately designed nutritional treatment regimen can enable individuals with PKU to achieve and maintain normal intellectual development.
Phe is an essential amino acid, meaning that it cannot be made in the human body and must be obtained from food sources. Phe’s essential nature has allowed for the development of nutritional treatment for PKU that remains the standard of practice today. Dietary Phe from intact protein sources can be restricted to the amount that allows for normal growth and development while preventing excessive build-up of Phe in the blood. A dietitian with special training develops an individualized diet plan for each person with PKU. The plan is adjusted over time to accommodate changes in life stage and health status. The steps to create the diet are as follows:
See Table 2 for a sample daily menu for a 9-year old child with PKU. The menu includes a medical food that provides Phe-free protein; foods modified to be low in protein; and the modest allowable amount of intact protein from fruits, vegetables, and grain based products.
Although the amount of dietary Phe that individuals with PKU tolerate varies , clinical observation suggests that most children, adolescents, and adults with PKU tolerate between 250 and 450 mg of dietary Phe per day (personal communication, Kathleen Huntington, May 1, 2012), which is the amount of Phe in 5 to 9 grams of intact protein or 1.5 to 3 slices of bread . Clearly, no individual of any age would survive if he or she consumed only this amount of protein. Medical foods and foods modified to be low in protein were developed to provide adequate nutrition for body growth and maintenance. Without these foods, the low protein and calorie intake associated with the need to restrict dietary Phe would result in malnutrition severe enough to be incompatible with life. These special foods also help people with PKU obtain sufficient calories to prevent breakdown of muscle tissue, which would release Phe into the bloodstream.
Balancing Phe tolerance with energy needs in people with PKU becomes significantly more difficult with age. An adolescent male aged 15 to 19 years requires 3,000 calories per day, yet his Phe tolerance might only be marginally higher than that of a 9-year-old child . If adults with PKU do not control their dietary Phe intake through nutritional treatment, they lose neurocognitive function. Furthermore, insufficient dietary control very early in and throughout pregnancy in women with PKU results in maternal PKU syndrome, which is associated with microcephaly, intellectual disability, cardiac defects, and growth failure in offspring.
Nutritional products for IEM treatment include two different forms of medical foods—one containing protein without the offending amino acid(s) and the other consisting of foods that have been modified to be low in protein. For example, medical foods for PKU provide the protein required for normal growth and development with no or negligible amounts of Phe. The majority, but not all, of these products also include other nutrients (such as fat, carbohydrate, vitamins, and minerals) needed to support normal nutritional status. These medical foods provide between 85 and 90 percent of the protein needs of an individual with PKU and are therefore a critical component of PKU treatment. Foods modified to be low in protein are an alternative to foods that must be excluded from or severely limited in a PKU diet. Modified low-protein foods include breads, pasta, cereals, and baked products made with low-protein flours. People with PKU and other IEM need these products to provide energy and satiety.
For many IEM, single amino acids and amino acid mixtures, vitamins, and other compounds are used to replace conditionally essential nutrients or enhance enzyme activity. For example, arginine must be supplemented in the diets of individuals with certain urea cycle disorders because their bodies produce insufficient amounts.
The products used to treat IEM are referred to in the literature and by clinicians, patients and families, and manufacturers using a variety of terms. The inconsistent use of terms has led to confusion and misunderstanding regarding the clinical purposes of these products and this misunderstanding, in turn, affects access to these treatments.
The products used to treat IEM can be broadly categorized by purpose as follows: 1) those that provide the bulk of nutritional intake for individuals with an IEM, specialized for a specific disorder, and include protein and a range of other nutrients but not the offending amino acid(s); 2) those that are modified to be low in protein; and 3) those that are single amino acids, amino acid mixtures, vitamins, or other compounds used to replace conditionally essential nutrients or to enhance enzyme activity. A more detailed description of these products, their intended use, and companies that manufacture and/or distribute them follows in Sections 3.1.1 and 3.1.2 and Table 3 below.
In the United States, the Food and Drug Administration (FDA) regulates infant formulas developed for IEM and categorizes these formulas as “exempt.” These formulas must meet the same regulatory requirements as standard infant formulas, except that FDA does not require them to include the offending nutrient(s); for example, products designed for PKU do not include Phe .
The term “exempt” may be misleading because it implies that these formulas are exempt from all regulations, which is not the case. Manufacturers must provide a detailed description of the medical condition that the formulas are designed to treat, the rationale for the deviation from a standard infant formula, and a specific disease claim for the product’s use (e.g., for use in PKU) . New exempt infant formulas require a 90-day premarket notification to FDA by the manufacturer. The exempt infant formulas used to manage IEM are generally represented and labeled solely to provide dietary management for a disease or condition that is clinically serious or life-threatening and patients must use these formulas for prolonged periods . Although infant formulas for IEM are also considered to be medical foods (discussed in Section 3.2.2 below), they are regulated as infant formulas.
Medical foods for children over age 1 year and for adults are designed to treat a specific condition, so they are exempt from the nutrition labeling, health claims, and nutrient content claims requirements of the Nutrition Labeling and Education Act of 1990 . They must, however, meet the requirements of good manufacturing practices.
Products manufactured for the nutritional treatment of IEM are considered medical foods as defined by the Orphan Drug Amendments of 1988 :
… 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.
Further information on the definition of a medical food is available in FDA’s Compliance Program Guidance Manual, which includes the following expanded definition :
Generally, to be considered a medical food, a product must, at a minimum, meet the following criteria:
Medical foods are distinguished from the broader category of foods for special dietary use and from foods that make health claims by the requirement that medical foods are to be used under medical supervision. The term “medical foods” does not pertain to all foods fed to sick patients. Medical foods are foods that are specially formulated and processed (as opposed to a naturally occurring foodstuff used in its natural state) for the patient who is seriously ill or who requires the product as a major treatment modality. Typical medical foods are enteral nutrition products, i.e., products provided through the gastrointestinal tract, taken by mouth, or provided through a tube or catheter that delivers nutrients beyond the oral cavity or directly to the stomach. [Boldface added for emphasis by the authors.]
Foods modified to be low in protein are manufactured specifically for protein-restricted diets that require medical supervision, such as the diets that people with PKU must follow. These foods are generally labeled as such.
Medical foods (with the exception of infant formulas, as discussed in Section 3.2.1 above), including foods modified to be low in protein, do not require premarket review and are not registered with FDA . However, like all food manufacturers, manufacturers that make medical foods must be registered with and are inspected by FDA .
Single amino acids and amino acid mixtures, vitamins, and other compounds are often used to replace conditionally essential nutrients or enhance enzyme activity in patients with IEM. FDA classifies single amino acids, amino acid mixtures, vitamins, and several other compounds used to treat IEM as dietary supplements. These products must meet the requirements of the Dietary Supplement Health and Education Act . Generally, manufacturers do not need to register these products with FDA or obtain FDA approval before producing or selling them. However, manufacturers are responsible for ensuring that the dietary supplements they manufacture are safe before marketing these products. FDA may take action against any unsafe dietary supplement product after that product reaches the market.
L-carnitine, a product used in specific IEM to replace this conditionally essential nutrient and/ or assist in the excretion of toxic metabolites, can be obtained as both a prescription drug (Carnitor® by Sigma Tau) and a dietary supplement.
With the exception of Carnitor®, FDA does not regulate dietary supplements used to replace conditionally essential nutrients or enhance enzyme activity in patients with IEM as drugs. These products are, however, often given to patients in doses that far exceed DRI levels and their use in IEM closely approximates the action of drugs. The term “pharmacological dose” is often used to describe the large doses of dietary supplements used in IEM. However, strictly speaking, the term “pharmacologic” is misapplied to these products because they are not defined or regulated as drugs in the United States.
In general, and, with the exception of federal health insurance programs, such as TRICARE® (the health care program for uniformed service members, retirees, and their families), what is covered by insurers is determined by state regulations and policies. No national or uniform policy addresses coverage for medical foods for individuals with IEM. Individuals with IEM, including PKU, obtain medical foods through a number of mechanisms, including distribution programs associated with metabolic clinic and state newborn screening programs, pharmacies, home health care companies that provide durable medical equipment supplies, and manufacturer ordering programs. The source used to obtain medical food products depends on where the patient lives and whether third-party payers cover the products’ costs.
Dispensing entities and manufacturers typically require authorization from a medical professional before dispensing a medical food to a patient to prevent inappropriate use of these products. The authorization for the product from a medical professional specifies the amount of medical food that the patient needs based on his or her age and nutritional requirements. This authorization is often written as a “prescription.” However, these products are not regulated as drugs and the use of the term “prescription” has been a source of confusion with respect to reimbursement. Clinicians recommend foods modified to be low in protein but patients typically purchase these products through mail order without needing to obtain medical authorization first.
As per FDA regulation, medical foods are formulated to be consumed or administered enterally and are consumed orally or through a tube. Most individuals with IEM consume their medical food treatments by mouth. However, the Centers for Medicare and Medicaid Services (CMS) Healthcare Common Procedure Coding System (HCPCS) coding for provision of enteral formulas designates administration by feeding tube. In addition, the amount of medical food needed by many individuals with IEM is typically calculated based on grams of protein, yet CMS coding is based on calories. These discrepancies further exacerbate the reimbursement problem. See https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/downloads//ncd103c1_Part3.pdf for coverage regulations. Of note is that CMS does not include the term “medical food” in its HCPCS coding language.
Some states provide coverage of medical foods for people with IEM through their state public health newborn screening programs. Thirty-eight states have enacted legislation that requires insurers to provide coverage for medical foods for at least PKU; over a third of these states require coverage for all IEM . States generally do not provide coverage beyond the age of 18 . Three-quarters of states that have passed mandates require coverage for foods modified to be low in protein .
Insurance coverage is subject to the limitations of each policy, including co-payments, cost-sharing requirements, and deductibles. In addition, federal programs such as TRICARE® and policies that are certified by the Employee Retirement Income Security Act (or are self-insured) do not need to comply with state mandates. Medicaid covers the costs of medical foods in all but one state. Foods modified to be low in protein are less widely covered by third-party payers.
The estimated annual wholesale costs of medical foods supplying protein (excluding additional costs for foods that are modified to be low in protein, amino acids, vitamins, and other compounds) for amino acid disorders identified by state-based, universal newborn screening are shown in Table 4. For PKU, the average wholesale cost to supply DRI levels of protein  during the first year of life is estimated to be $1,248. As protein requirements increase into adulthood, the wholesale cost of medical foods supplying protein increases to an estimated $8,522 for late adolescent and adult males and during pregnancy.
Patients and insurance companies typically pay more than the wholesale cost for medical foods. Third-party durable medical equipment vendors and pharmacies increase the billed costs to insurance companies by as much as 200 to 300 percent of the wholesale cost. In some cases, families pay more than the wholesale price (through coinsurance) for products that insurance companies obtain through third-party vendors.
Foods modified to be low in protein cost two to eight times as much as their regular counterparts. These foods are rarely available in retail stores, and their shipping and handling costs can be as high as $50.00. See Table 5 for examples of the costs of regular food options compared to the costs of similar foods modified to be low in protein.
Virtually every newborn in the country is screened early to identify IEM and other disorders through universal state-based newborn screening programs. These programs began over half a century ago and have expanded over the years to identify more than 30 disorders. Most IEM that require medical foods are detected through these efforts. Nutrition treatment is the standard of medical care for many disorders identified through newborn screening, yet affected individuals do not necessarily have access to appropriate treatment. Systemic problems that have contributed to this paradox include the lack of robust, evidence-based research documenting the effectiveness of treatments and inconsistent access to these treatments.
Individual IEM are rare and each has a unique etiology, pathophysiology, and response to therapeutic interventions. IEM are generally identified in infancy and have a very narrow window of treatment opportunity. Randomizing patients with IEM into treatment or control arms in clinical trials is generally not possible because assigning infants or children with IEM to a placebo group would be unethical. Although efforts are underway to evaluate the evidence and design nutritional guidelines for IEM treatment, little information in this area of patient management has come from rigorous, controlled research studies. In this era of health care reform, a greater investment in evidence-based research for the treatments used in IEM has become critical.
Nutritional treatments are regulated under FDA food and dietary supplement regulations, not regulations that govern “drugs.” Unlike regulated drugs, these treatments do not require a “prescription.” They are viewed as “food” and “supplements,” which exacerbates the difficulty of obtaining third-party payer reimbursement for these products. In addition, the use of inconsistent terminology when referring to medical foods and dietary supplements and the misuse of words that imply that these products are regulated as drugs lead to confusion. The appropriate and effective use of medical foods and select dietary supplements for IEM is constrained by discrepancies in terminology and misunderstanding regarding the regulation of these products.
Although 38 states require coverage of medical foods by third-party payers, many inconsistencies and loopholes remain in medical food coverage. Currently, a patchwork of coverage exists, ranging from selective coverage of medical foods for specific disorders, termination of benefits in late adolescence, failure to cover treatment during pregnancy, and restrictions on the types of medical foods covered, to caps on the dollar amount covered.
In April 2009, the HHS Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children recommended insurance coverage for IEM, tying their recommendation for coverage to the Secretary’s recommended uniform screening panel (which is covered by the Patient Protection and Affordable Care Act) . The committee characterized individuals identified through newborn screening who require specific treatments to be at high risk and recommended that HHS regulations ensure that these individuals have access to comprehensive treatment coverage.
Access to treatment for IEM is an essential component of the of the public health newborn screening system, the goal of which is to prevent adverse outcomes in individuals who are affected by these disorders. Improving patient access to nutritional treatments for IEM should start by harmonizing definitions and interpretations of statutes used to describe and regulate nutritional treatments for IEM. Educating state policymakers about nutritional treatments for IEM could lead to improved health insurance coverage of IEM treatments.
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the NIH or the US Department of Health and Human Services.
1IEM: inborn error of metabolism; HHS: Health and Human Services; PKU: phenylketonuria; Phe: phenylalanine; Tyr: tyrosine; DRI: Dietary Reference Intake; FDA: Food and Drug Administration; CMS: Centers for Medicare and Medicaid Services; HCPCS: Healthcare Common Procedure Coding System
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.