Successful intervention for inborn errors of metabolism (IEMs) is a triumph of modern medicine. For many of these conditions, medical foods are the cornerstone of therapy and the only effective interventions preventing disability or death. Medical foods are designed for patients with limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foods or nutrients, whereby dietary management cannot be achieved by modification of the normal diet alone. In the United States today, access to medical foods is not ensured for many individuals who are affected despite their proven efficacy in the treatment of IEMs, their universal use as the mainstay of IEM management, the endorsement of their use by professional medical organizations, and the obvious desire of families for effective care. Medical foods are not sufficiently covered by many health insurance plans in the United States and, without insurance coverage, many families cannot afford their high cost. In this review, we outline the history of medical foods, define their medical necessity, discuss the barriers to access and reimbursement resulting from the regulatory status of medical foods, and summarize previous efforts to improve access. The Advisory Committee on Heritable Disorders in Newborns and Children asserts that it is time to provide stable and affordable access to the effective management required for optimal outcomes through the life span of patients affected with IEMs. Medical foods as defined by the US Food and Drug Administration should be covered as required medical benefits for persons of all ages diagnosed with an IEM.
Successful intervention for inborn errors of metabolism (IEMs) is a triumph of modern medicine. The prevention of severe intellectual disability, otherwise typical in untreated phenylketonuria (PKU), by treatment with a phenylalanine-restricted diet led to the development of newborn blood spot screening in the 1960s. States initiated public health programs to improve outcomes for infants who were affected by initiating treatment using a specially developed formula with a protein source extremely low in or devoid of phenylalanine.1 For >50 years in the United States, early dietary intervention has resulted in near-normal or normal development of individuals with PKU. The success of treatment of PKU led to advances in similar dietary interventions for other IEMs and the commercial production of medical foods for IEM treatment. For many of these conditions, medical foods are the cornerstone of therapy and the only effective interventions preventing disability or death.
Before 1972, metabolic formulas for IEMs were classified by the US Food and Drug Administration (FDA) as drugs. They were subsequently removed from the drug category. This change was made to reduce obstacles so that the formula industry would be better able to innovate, change, and make available these essential medical interventions.2 In 1988, the term “medical food” was defined in section 5(b) of the Orphan Drug Act (ODA)3 as follows:
[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.3
By establishing this definition, the ODA recognized the importance of these products for medical management and began the process of regulating this category. In 2016, the FDA published its most recent guidance for industry, which further specified the conditions and products that fit the ODA definition. The guidance specifically indicated that medical foods are specially formulated and processed (as opposed to naturally occurring) and are designed for partial or exclusive feeding orally or by tube. Most notably, they are designed for patients with limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foods or nutrients, whereby dietary management cannot be achieved by modification of the normal diet alone. They are to be used to manage the unique nutrient needs of a specific disease or condition determined by medical evaluation and are intended for a patient receiving active, ongoing medical supervision.4 The community of providers and families had long hoped that the classification of products to be used in the management of IEMs as a defined entity, medical foods, would facilitate access, in part, by improving insurance coverage.
In the United States today, access to medical foods is not ensured for many individuals who are affected despite their proven efficacy in the treatment of IEMs, their universal use as the mainstay of IEM management, the endorsement of their use by professional medical organizations, and the obvious desire of families for effective care. Medical foods are not sufficiently covered by many health insurance plans in the United States, and without insurance coverage, many families cannot afford their high cost.
PKU, as the first screened condition, serves as a paradigm disorder to illustrate this remarkable inconsistency in access to medical food. Without access to medical food, individuals with PKU are forced to suffer the consequences of toxic elevated levels of phenylalanine and its metabolites in the blood and brain. These abnormal levels have developmental, behavioral, and mental health consequences that include difficulties in school, work, and relationships. Moreover, some individuals who are affected experience long-term neurologic damage related to failure to maintain dietary control.5 For individuals with other IEMs, lack of access to medical foods leads to growth failure and even to metabolic crisis, with permanent neurologic damage and death.6
Despite the proven outcome of these effective interventions, children and adults with PKU and other IEMs often struggle to obtain insurance coverage for their essential treatment.7 Thus, access to medical foods is not ensured. Lack of insurance coverage is an even greater problem for adults affected with IEMs. In this review, we will outline the history of medical foods, define their medical necessity, discuss the barriers to access and reimbursement resulting from the regulatory status of medical foods, summarize previous efforts to improve access, and offer approaches for resolution of these issues.
Medical Foods Are Essential Management Modalities for IEMs, Including Many That Are Identified by Newborn Screening
National Mandate for Newborn Screening: Relationship to Medical Foods
Newborn screening is a successful preventive public health program,8 an essential health benefit,9 and an established medical practice.10 The use of medical foods is necessary to achieve the benefits of newborn screening. The success of PKU newborn screening and subsequent treatment with dietary intervention by using medical foods prompted screening for other conditions amenable to intervention. Increasing variation in conditions screened from state to state occurred as states expanded newborn screening panels. Some states added many new conditions to their newborn screening programs; other states did not. This, along with other factors such as the development of new screening methodologies, led to calls for the evidence-based Recommended Uniform Screening Panel (RUSP) to provide guidance to state newborn screening programs on conditions for which screening should be done. In developing the RUSP, many of the conditions on the initial panel were included on the basis of the utility of intervention with medical foods and/or amino acids, vitamins, or cofactors. An essential criterion for inclusion of a condition is the availability of an effective treatment.10 As such, the use of medical foods is necessary to achieve the benefits of newborn screening. Sixteen of the core conditions recommended for screening employ medical foods as their primary intervention for successful treatment.6 In addition to the conditions on the RUSP, there are other similar IEMs for which no newborn screening test is currently available (eg, ornithine transcarbamylase deficiency) but for which medical foods are required as their essential interventions. For these conditions, treatment is initiated after clinical diagnosis.
What Are the Consequences of Failing To Use Medical Foods in Treatment of IEMs?
Failure to initiate treatment with required medical foods results in significant morbidity and, in some conditions, mortality. For example, individuals with untreated PKU suffer significant cognitive impairment, autistic-like features, and adult-onset psychosis.11 Because high phenylalanine levels significantly impair fetal brain and heart development, pregnant women with untreated PKU will most likely bear children with maternal PKU syndrome, a condition that includes intellectual disability, small head size, and heart defects. Maternal PKU syndrome is prevented if the fetus is not exposed to excessive phenylalanine during gestation.12 Individuals with untreated homocystinuria suffer cognitive impairment, lens dislocation, skeletal deformities, and increased risk for stroke and heart attack.13 Individuals with untreated very-long-chain acyl-Coenzyme-A dehydrogenase deficiency may suffer hypoketotic hypoglycemia, leading to death or severe impairment, and may have cardiomyopathy or growth failure.14 Each condition could be characterized similarly; they were included in the RUSP because of clear evidence that treatment, typically related to the use of medical foods, improved outcomes.
Because all the screened conditions included on the RUSP that are amenable to intervention with medical foods are genetic disorders, they are permanent. Although the likelihood for severe metabolic decompensation varies through the life span and with each individual condition, optimal outcome requires lifelong treatment. For example, the American College of Medical Genetics and Genomics recently published guidelines for PKU strongly endorsing lifelong treatment, citing later-onset complications of treatment discontinuation.15 Genetic Metabolic Dietitians International published evidence-based guidelines for nutritional management for PKU for persons affected of all ages reinforcing these concerns and defining how treatment should be performed.16 Despite this knowledge and these recommendations, it is estimated that more than half of adults with PKU are not being managed and are likely untreated.17
Poor outcomes for individuals affected can result from failure to use medical foods at all but can also result from insufficient treatment with medical foods, as is seen when a family can afford only part of the prescribed medical food. The costs (including, but not limited to, cost in dollars) to the individual, family, and society include the following:
the cost of caring for an individual with IEMs who has intellectual disability that could have been prevented by appropriate treatment18 ;
birth defects and intellectual disability in the offspring of a woman with PKU who was not treated before pregnancy12 ;
loss of life either because of metabolic crisis or because of consequences of inadequately treated IEMs; and
development of incapacitating problems in adults who were treated as children and lost access to medical food as adults. For example, this would include strokes in individuals with homocystinuria and neurologic and mental health problems in individuals with PKU, with increases in failures in school, work, and relationships for those who were previously successful.
How Many Persons Are Impacted by a Need for Medical Foods?
All of the conditions included on the RUSP are rare on the basis of the definition provided in the 1983 ODA, meeting the criterion of occurring in <200 000 Americans. Therrell et al6 summarized data regarding positive cases identified by newborn screening from 10 years of reporting from the National Newborn Screening Information System (2001–2011). This information was provided voluntarily by states and represents a minimal estimate of the numbers of individuals affected. These data did not include individuals requiring medical food who were diagnosed by means other than the newborn screen. Considering only the 16 core RUSP conditions requiring medical foods, this report revealed that 4822 individuals affected with a core RUSP condition were identified over that 10-year period.6
What Are Today’s Medical Foods?
The nature of medical foods has evolved remarkably through the years. Beginning with a single product for the treatment of PKU, currently there are many types of products available for most IEMs that respond to nutritional interventions. When dietary intervention was first developed a half century ago, diets for individuals with IEMs were inherently monotonous, unappealing, and unlike anything approaching a normal diet. Over the years, companies that manufacturer medical foods have gone to great lengths to improve nutrient composition, taste, palatability, and appearance to maximize nutritional status and patient compliance to these difficult dietary regimens. Additional manufacturers have entered the marketplace, and a variety of products for a much wider range of IEMs is now available. These products come in multiple forms and are designed to provide age-appropriate options for patients, including condition-specific infant formulas. Medical food products fall into 3 general categories: products in powder form or ready to drink that are devoid of the offending nutrient but are otherwise nutritionally complete; modular products that are not nutritionally complete but serve to provide a component of the diet devoid of the offending nutrient, such as amino acid mixtures, low-volume products, and tablets; and foods modified to be low in protein, such as baked goods, pasta, and meat and cheese substitutes that provide needed calories and satiety.
How Do the Statutes Currently Define Medical Foods, and How Are They Regulated?
Medical foods were distinguished from the category of foods for special dietary use in the regulations because they are intended for the specific dietary management of a disease or condition to meet the critical and distinctive nutritional requirements for that condition.19 Additional clarification from the FDA came with the guidance for industry released in 2016.4 This guidance indicated that medical foods are specially formulated and processed for partial or exclusive feeding orally or by tube; are designed for patients with limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foods or nutrients, whereby dietary management cannot be achieved by modification of the normal diet alone; and are to be used to manage the unique nutrient needs of a specific disease or condition determined by medical evaluation. They are required to be used for a patient receiving active, ongoing medical supervision and must be specially formulated for a patient who is seriously ill or who requires the product as a major treatment modality. These features do not pertain to all foods fed to patients who are sick. Examples of conditions for which the regulatory category of medical food would not apply include pregnancy, which is not a disease, and chronic conditions, such as diabetes and celiac disease, because these conditions can be managed with modification of a normal diet without the use of specially prepared licensed commercial products.
The Federal Food, Drug, and Cosmetic Act and the Fair Packaging and Labeling Act exempted medical food products from nutrition labeling, health claims, and nutrient content claims requirements. Ingredients must be approved food additives for the intended use or, if not, are generally recognized as safe or have an exemption for investigational use. Medical foods do not require premarket review or FDA approval, but manufacturers must be registered with the FDA, must comply with certified good manufacturing processes, and are inspected every 2 years. The FDA does not maintain a list of specific medical food products.
Medical foods intended for use by infants are regulated as infant formula. They are categorized as exempt but must meet the same regulatory requirements as standard infant formulas except that they are not required to contain the offending nutrient, the absence of which creates the medical foods’ effectiveness as a management modality for the respective IEM. These formulas have strict labeling requirements, and new products require a 90-day premarket notification to the FDA. Unlike medical foods developed for individuals >1 year of age, manufacturers who make medical foods for infants are inspected annually.
The 2016 FDA guidance also described what does not apply to medical foods. They are specifically not prescription drugs, they do not have National Drug Code codes, and they do not require a prescription. This clarification specifically identified IEMs as conditions that a medical food could be used to manage. It was further specified that medical foods could not be marketed for diseases and conditions for which a normal diet could be modified to adequately manage the dietary needs.
How Do Patients Access Medical Foods, and Who Pays for Them?
There is no uniform strategy for supplying medical foods to patients. Because medical foods are regulated as foods and not drugs, they may be referred to as over the counter; however, in most cases, authorization is required by the pharmacy, company, or organization dispensing the product to demonstrate supervision by a medical provider. In some cases, medical foods are dispensed in programs administered by states and are provided as part of their service infrastructure. This is undertaken either by a state directly or by metabolic clinics as part of arrangements with the state. Families may receive their medical foods from pharmacies, hospitals, health departments, medical supply companies, or medical food companies. Payment for medical foods may occur through programs administered by states (Medicaid, the Children’s Health Insurance Program, the Special Supplemental Nutrition Program for Women, Infants, and Children). Coverage of medical foods can also occur by using military health benefits by dependents of active duty service members and retirees. Coverage by private insurance is variable. Most medical food companies provide a small supply for patients newly diagnosed with a condition and provide some formula for pregnancies in women who are affected, but this practice must be viewed as a bridge until coverage from other sources can be obtained.5 Many families purchase medical foods out of pocket.7 The source of supply and coverage is thus highly variable and dependent on the age of the patient, their sex, the IEMs they have, where they live, and what health benefits they have.
As of 2016, 35 states had passed legislative mandates for state or private payer coverage of medical foods.19 Such coverage, mandated on a state-by-state basis, does not apply to those who are self-insured or where state law was not applicable (eg, federal plans). In addition, there is wide variability in coverage from state to state. The IEM community had hoped that the Affordable Care Act (ACA) might lead to improvement in access to medical foods, but the ACA did not specifically address medical foods; medical foods were not included as an essential health benefit, although newborn screening itself is a covered benefit without co-pay for families.
In 2016, the Catalyst Center, a national center for health insurance and financing for children and youth with special health care needs, prepared an update summarizing state statutes and regulations on dietary treatment of disorders identified through newborn screening. In this detailed assessment of current state-specific information, the center found extensive state-to-state differences in diagnoses covered, types of medical foods provided, the route of administration, age eligibility and benefit limits, and mandates for private insurance coverage resulting in major gaps for coverage and significant differences based on the state of residence.20 Coverage was highly dependent on the state in which the individual resided. The Catalyst Center report confirmed previously ascertained information regarding the highly variable nature of anticipated coverage and the state regulations governing this.
What Is the Cost to Families?
Although the vast majority of states have enacted laws requiring insurance companies to cover medical foods, self-insured plans are exempt from state laws regulating the business of insurance under the Employee Retirement Income Security Act and are not required to include medical foods as a covered benefit. Because approximately half of commercial health insurance plans are Employee Retirement Income Security Act plans, state insurance regulation has not provided a consistent or robust safety net to guarantee affordable access to medical food. The out-of-pocket costs of medical foods depend on the individual’s age, the disorder, and insurance coverage status. Therrell et al6 estimated that annual costs for treating a person with an IEM versus a person without an IEM ranges from $2254 for an infant to almost $25 000 for a man or pregnant woman.
Again, using PKU care as an example, in 2012 Camp et al21 estimated that the annual wholesale cost to provide medical foods (medical formula only) for an infant was $1248; for a child in elementary school, the annual cost was $2643, and for a man, the cost was $8522. It is important to note that patients and insurance companies typically pay as much as 200% to 300% of these wholesale costs. The products vary in cost depending on the amount needed to feed an individual, with products intended for use by children costing approximately twice as much as products for infants. Medical food costs also vary depending on the disorder intended for treatment. At the time this article was written, one wholesale site listed Phenex-2 (used in the management of PKU) at $313.39 per case of 6 14.1-oz canisters, whereas Propimex-2, Hominex-2, and Valex-2 (for propionic and methylmalonic acidemia, homocystinuria, and disorders of leucine metabolism, respectively) were priced at $576.14 per case.22–25
Medical food products are more expensive than standard formulas. For perspective, Phenex-1, an infant formula to treat PKU, costs $33 per can, $0.17 per kilocalorie provided in the formula.26 Similac powder, a comparable infant formula that is not a medical food, costs $16 per can, $0.088 per kilocalorie.27 The feedings prepared for an infant may contain both of these products. The daily recipe for a typical 4-month-old infant would contain 85 g of Phenex-1 and 65 g of Similac, costing respectively $6.97 and $2.92 for a total cost per day of $9.89. If the infant did not require medical foods and was fed a similar amount regarding caloric intake of Similac only, the cost would be $6.52 per day. Overall, the medical foods for infants with PKU, which are the lowest cost of an IEM medical food, are approximately twice what is standard. Moreover, formula costs rise considerably for rarer IEMs.
In addition to medical foods, the inclusion of foods modified to be low in protein in daily meals not only provides needed calories but also saves costs when these foods are used as an energy source versus medical foods alone. Huntington and Buist28 analyzed the cost comparison of a combination therapy of medical foods and foods modified to be low in protein versus medical foods’ protein as a primary energy source for a 9-year-old child with PKU. If medical foods are the predominant energy source, the cost of treatment is 170% more than using a combination of medical foods and foods modified to be low in protein, which would realize a savings of $8000 per year.28 Although their use reduces the cost of dietary management overall, it should be noted that foods modified to be low in protein are 2 to 8 times more expensive than their regular counterparts and typically must be specially ordered and shipped through a medical foods company. For example, Camp et al21 estimated that the cost per 100 g of regular spaghetti is $0.37, whereas the low-protein version is $2.20 per 100 g. Despite their costs, foods modified to be low in protein are an integral part of dietary management for IEMs, for which protein must be restricted. They allow the person affected to meet needed energy requirements, providing satiety and alternatives to standard foods that must be excluded or severely limited from the diet.
History of Remediating Efforts
The Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) has long recognized the inherent contradiction of requiring screening without ensuring treatment. Written communications specifically addressing medical foods from the ACHDNC to the Secretary of the Department of Health and Human Services in 2007, 2009, and 2010 recommended addressing gaps in coverage and reimbursement and urged a more uniform approach to coverage, specifically requesting that Medicaid regulations be amended to extend uniform coverage to all states. No actions directed at coverage for medical foods have resulted from these communications.29
External to the ACHDNC and its subcommittees, several federal legislative initiatives have been undertaken. The Medical Foods Equity Act of 201130 included provisions that federal health programs and private insurance companies cover “medically necessary food” and “pharmacologic doses” of vitamins and amino acid supplements as prescribed by qualified medical providers. It amended the Social Security Act definition of these products specifically for conditions as recommended by the ACHDNC. The Medical Foods Equity Act of 201331 used the same language and descriptors but removed the requirement for private insurance companies to cover these products. Although these provisions would have improved access and management for persons with IEMs, neither version of the legislation was enacted. A similar bill, the Medical Nutrition Equity Act of 201732 has recently been introduced. The American Health Security Acts of 2011,33 2013,34 and 201535 proposed coverage for medical foods and reiterated the 1988 medical food definition, but no committee action occurred to enact this legislation. Of note, federal action for medical food coverage has taken place in one specific area: that of coverage by Tricare, the health care program for uniformed service members and their families.36
The 2017 revision to the National Defense Authorization Act defining Tricare benefits notably improved coverage for families with a member affected with an IEM. Medical foods, medical equipment and supplies to administer, medically necessary vitamins, and modified low-protein foods ordered by a medical provider were all specifically included benefits on the basis of descriptions found in the FDA guidance. The legislation exempts specific conditions (gluten sensitivity, diabetes, and weight loss products) but specifies coverage for RUSP disorders as well as a list of IEMs not on the RUSP but treated similarly. Coverage is also mandated for medical foods used to treat a specified list of gastroenterological disorders.36 This language is mirrored closely in House of Representatives bill 2587, the 2017 Medical Nutrition Equity Act.32
Advocacy organizations (eg, the National PKU Alliance and the National Organization for Rare Disorders) have strongly encouraged coverage through positions on medical food coverage in the ACA, have urged appropriate education about coverage, have sought appropriate coding for billing, and have interacted directly with the FDA regarding the definition of medical foods. They led the way in advocacy for federal legislation and created position statements.37,38 Despite concerted and thoughtful advocacy, little effect on regulation has occurred. Professional organizations (eg, Genetic Metabolic Dietitians International, the American College of Medical Genetics and Genomics, the Society for Inherited Metabolic Disorders, the American Medical Association, and the American Academy of Family Physicians) have also created policy statements and, more recently, several professional guidelines describing the essential character of these interventions and providing details about management that can be used to guide appropriate coverage.15,16 The problem has been well described in the medical literature and at scientific consensus conferences (eg, Camp et al39 ), highlighting the necessity of establishment of uniform policies and strategies to remove financial barriers for appropriate treatment. The literature also describes a central barrier in attaining uniform access: laws and mandates regarding coverage are established on a state-by-state basis, with varying state laws and programs.
IEMs are included on the RUSP because effective interventions are available, but financial barriers interfere with access to those interventions for a significant number of patients and their families. Patients and families continue to be saddled with high costs for medical foods, and metabolic care teams spend significant time dealing with coverage and reimbursement requirements, leaving less for patient care and research. Families also spend significant time attempting to obtain coverage and reimbursement, leaving less time for normal life experiences and causing chronic anxiety about access to necessary treatments. Legislation has been introduced, advocates have spoken, professional organizations have provided expert opinion and recommendations, but the division of responsibilities between federal and state regulators as well as ambiguities about the regulation of medical foods has resulted in costly inaction. The recent inclusion of medical foods, the medical equipment and supplies to administer them, the medically necessary vitamins, and the modified low-protein foods ordered by a medical provider as Tricare benefits in the 2017 revision to the National Defense Authorization Act36 is evidence that a uniform approach to access can be achieved.
It is time to provide stable and affordable access to the effective management required for optimal outcomes through the life span of patients after identification of an IEM either by newborn screening or clinical diagnosis.
The ACHDNC affirms the following principle: medical foods, as defined by the FDA, should be covered as required medical benefits for persons of all ages who are diagnosed with an IEM (whether specified on the RUSP or identified in clinical practice) when the medical food requires authorization by a medical provider, the patient requires ongoing medical supervision, and dietary intervention cannot be achieved by modification of a normal diet alone. Accomplishing this task will require planning and communication among all stakeholders. Recognizing the complexity of the actions required to accomplish comprehensive coverage for medical foods, the ACHDNC recommends a meeting of stakeholders to reach an agreement on how best to accomplish this goal expeditiously.
Members of the Follow-up and Treatment (FUTR) Workgroup for the ACHDNC (in alphabetical order) are as follows: Jeffrey P. Brosco (University of Miami; Chair, FUTR Workgroup), Amy Brower (American College of Medical Genetics and Genomics), Debra Freedenberg (Texas Department of State Health Services), Kathryn Hassell (University of Colorado Denver), Christopher A. Kus (Association of State and Territorial Health Officials; Co-Chair, FUTR Workgroup), Nancy Doan Leslie (Cincinnati Children’s Hospital Medical Center), Sylvia Mann (Hawaii State Department of Health), Kamila B. Mistry (Agency for Healthcare Research and Quality Office of Extramural Research Education and Priority Populations), Jana Monaco (Organic Acidemia Association), Robert J. Ostrander (State University of New York Upstate Medical University), Margie A. Ream (Nationwide Children’s Hospital), Annamarie Saarinen (Newborn Foundation), Joseph H. Schneider (University of Texas Southwestern), Janet Thomas (Children’s Hospital Colorado), and Alan E. Zuckerman (Georgetown University).
This article was written for the committee report entitled “Medical Foods for Inborn Errors of Metabolism: The Critical Need to Improve Patient Access.”
Dr Berry wrote the manuscript on the basis of a presentation by Ms Camp, with immediate feedback and revision from Dr Greene and Ms Brown. Drs McDonough and Bocchini extensively reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
The views expressed herein are solely those of the authors and do not necessarily reflect the views of the Secretary of the US Department of Health and Human Services or of the individual members of the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.