Regulatory Focus™ > News Articles > Intractable Epilepsy and the Value of Formulated Ketogenic Diet Products

Intractable Epilepsy and the Value of Formulated Ketogenic Diet Products

Posted 18 October 2017 | By Eric Kossoff, MD 

This article discusses the benefits of the Ketogenic Diet (KD) and the Modified Atkins Diet (MAD) for adults and children as treatments for intractable epilepsy. It offers a patient-oriented interpretation of regulatory requirements for medical foods as well as study data demonstrating KD efficacy. The article was based on a presentation given at the 2017 RAPS Convergence, during the medical food session on Modification of Diet Alone (MODA) vs. access and convenience matters.

What is the ketogenic diet?

Epilepsy is a chronic, neurological disorder that causes a disruption of the brain's internal system of electrical communication. Intractable epilepsy is characterized by frequent and prolonged seizures, sometimes occurring dozens of times a day. There are many treatment options, including medications, devices and surgery. Fortunately, there is also an effective, non-invasive approach to support the management of intractable epilepsy shown to have proven value – the Ketogenic Diet (KD). KD is now an established, effective, non-pharmacological routine for intractable childhood epilepsy, provided throughout the world with variations in administration, of which one approach is the Modified Atkins Diet (MAD).

KD is a high fat, very low carbohydrate, moderate/adequate protein diet that has evolved from one of the oldest diet-related epilepsy treatments – fasting. Fasting was used as a treatment for reducing epileptic seizures for a very long time, before the advent of modern medicine.1 By the early 20th century, researchers were reporting improvements in seizure frequency after two or three days of fasting, suggesting that the change in metabolism, caused by avoiding carbohydrates, forced the body to use stored fat for energy.2 This led to the development during the 1920s by researchers of the 'classical' ketogenic diet, a diet aimed at achieving ketosis, i.e., a state mimicking the normal metabolic process where the body does not have enough glucose for energy so burns stored fats instead, resulting in a build-up of acids, called "ketones," within the body.

The ketogenic diets were nearly forgotten with the advent of the drug phenytoin in 1938. However, by the late 1980s and early 1990s, KD had found new, science-based advocacy along with a new, similar diet called the Modified Atkins Diet (MAD) developed at Johns Hopkins in 2001. Over the last decade, KD has had documented success in reducing the frequent daily and debilitating seizures for children with intractable epilepsy.

Where do medical foods fit within the KD and MAD diets?

Regulatory Considerations

Currently, the only food category legally permitted to make claims for the dietary management of disease or medical condition is what is defined by regulators as "medical food." Medical foods must be foods that can be taken orally or delivered through a feeding tube. They also must be labeled for the dietary management of the specific disorder, disease or condition for which they are intended. They are administered 'under medical supervision' to meet the medically-determined nutrient requirements of a patient.

Medical foods are formulated for managing diseases accompanied by distinctive nutritional needs that cannot be met by normal diet. In the US, medical foods are defined by the Food and Drug Administration's 1988Orphan Drug Act Amendments and fall under the general food and safety labeling requirements of the Federal Food, Drug, and Cosmetic Act, as regulated by the US Food and Drug Administration under the Food Drug and Cosmetic Act regulations, 21 CFR 101.9(j)(8).3

As defined in section 5(b) of the Orphan Drug Act (21 U.S.C. 360ee (b)(3)), a medical food is a food "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."

Two important regulatory questions impact patient access to specialized products designed to be used either as part of the KD and/or MAD. First, do these diets fall under the definition of "medical food" so that they can be clearly indicated for their intended patient population, and secondly, are they recognized as part of the medical management of the patient and therefore included in reimbursement coverage?

Those who manufacture medical foods must comply with two regulatory requirements. First is the US FDA's definition for medical food that requires evidence that the food in question provides "nutritional support for the management of the unique nutrient needs that result from a specific disease or condition …" Secondly, it must be demonstrated that "modification of the normal diet alone" (MODA), is not achievable and in a way acceptable to the regulator. Theoretically, diets can be modified in a number of ways, but a manufacturer of medical food, relying on the medical and nutritional expertise advice from healthcare professionals, including medical associations, must specify why it is impractical, unsafe, or even impossible for patients to meet their Distinctive Nutritional Requirements (DNR) through a modified diet.4

The Ketogenic Diet Center and Adult Epilepsy Diet Center

At the Johns Hopkins Ketogenic Diet Center in Baltimore, Maryland, both children and adults are treated with intractable epilepsy. KD has been managed through the Pediatric Epilepsy team at Johns Hopkins since the 1920s. Children starting the classic KD are admitted to the hospital as the high fat, very low carbohydrate diet needs to be carefully monitored and calculated by a knowledgeable physician over several days. The diet is challenging, especially at the beginning, and requires strict compliance, precise food measurements, patience, and careful observation. In many ways, KD is both an art and science, and accordingly, both diets must be "fine-tuned."

Traditionally, children are started on KD gradually, staying in the hospital over a two to three-day period after a 24 hour fast. The ratio of fats to carbohydrates and protein varies from 4:1 to 3:1 for infants and adolescents. Calories and fluids are carefully measured as are solid foods and/or the KD formula. Families of those children on KD are updated and educated daily.

Kossoff Figure 1

Adults beginning MAD in the Adult Epilepsy Diet Center do not need to be hospitalized. The adult clinic, which opened in 2010, and is the first-ever clinic specially designed for epilepsy diet management in adults.

Study Results

The mechanisms by which KD benefits seizure control are not fully understood and are likely multiple. There have been impressive results from studies investigating the efficacy of KD for children and MAD for adults. For example, in a study published in 2010 in the Journal of Child Neurology,5 MAD augmented by a specially formulated KD product ("shake") was effective for managing intractable childhood epilepsy. The open-label, prospective study investigated a Modified Atkins Diet with supplemented with 60 g/day of ketogenic 4:1 powder for the first month. Of the 30 children, 87 percent drank KD as liquids. For the second month, they had MAD alone. At one month, of the 30 children receiving treatment, 24 (80 percent) had a greater than 50 percent seizure reduction, of which 11 (37 percent) had a greater than 90 percent seizure reduction. There was no significant loss of efficacy during the second month of the study when the KD component was discontinued.

Case Study

A 17-year-old female with 10-year history of weekly seizures due to genetic epilepsy who failed to respond to six anti-seizure drugs sought a new treatment. Her family used the Internet to ask a neurologist about ketogenic diets. They were told that KD was "too difficult for normal teenagers." However, the family contacted The Charlie Foundation6 and the Foundation recommended the adult clinic. When she and her parents visited the outpatient Adult Epilepsy Diet Center, the Modified Atkins Diet was recommended and provided two hours of group instruction on foods to eat. At one week, there was no change in her seizures. She reported that she liked the fat foods, but she missed eating rice and pasta. However, at one month, her seizures had been reduced by 90 percent. She tried ketogenic shakes and bars, but found them "too sweet." At two months, she "cheated," but had no seizures; she stopped the diet and her seizures increased.

Both KD and MAD are strict diets where a small indiscretion of carbohydrates has major implications. This reality highlights two problems, both of which are illustrated in this case study. First, epilepsy is a private disorder, but eating ketogenic diet foods is not. In adults, about 50 percent are noncompliant with KD by six months. Second, the family did not have cost reimbursement. Families are mostly on their own in terms of expense associated with the diets.

What Patients and Their Families Need and Want

Poor adherence to KD has been an important factor to consider. For example, in a 2005 study, only 50 percent of children receiving the oral ketogenic diet remained on the diet after one year.7 However, things have improved since and the success of both KD and MAD in managing patients with epilepsy is well-documented.8 But there is still work to be done and we listen to patients and their families when they tell us how difficult this diet can be.

By and large, patients and their families are asking more lately for pre-made foods that mimic "normal" snacks. They want KD foods to have "crunch," and they would like the foods to be portable, with no refrigeration required. They do not want foods that are too sweet. Most of all, they want inexpensive foods or perhaps even better, KD diet insurance coverage. A clear regulatory product status helps with patient adherence, as well as reimbursement.

How can products help KD patients?

There are several types of products that can assist patients in achieving success in the KD. For example, at many recent ketogenic diet conferences, vendors brought new food products including a variety of sweeteners and taste enhancers. They also offered products designed to mimic normal foods such as breads, pizzas, brownies, and cookies that are for sale. Several charity groups and even organizations like Quest have started to make "keto" products as well for sale.

Medical foods currently used in the KD for the dietary management of intractable epilepsy are a good example of the need to consider the overall management of the disease in a patient-oriented way as they can serve as an enabler to improve adherence of patients to a diet often too strict to comply with over an extended time.

Regulators are invited to enter into a constructive dialogue with all vested stakeholders to develop guidance documents that are true to science and to the needs of the patients. This may be seen as part of an overall effort to foster innovation and the development of safe and clinically effective products that would play a vital role to improve overall outcomes in the disease management.

References

  1. Roehl, K. and Sewak, S.L. "Practice Paper: Classic and Modified Ketogenic Diets for Treatment of Epilepsy." Journal of the Academy of Nutrition and Dietetics, 2017;117:1279-1292.
  2. Ibid.
  3. FDA, 21 CFR 101.9(j) (8).
  4. Giordano-Schaefer, J., Ruthsatz, M. and Schneider, H. "Distinctive Regulatory Barriers for the Development of Medical Foods." Regulatory Focus. October 2017. Regulatory Affairs Professionals Society.
  5. Kossoff, E.H., Dorward, J.L., Turner, Z., Pyzik, P.L. "Prospective of the Modified Atkins Diet in Combination With a Ketogenic Liquid Supplement During the Initial Month." Journal of Childhood Neurology, 2011 Feb;26(2):147-51.
  6. The Charlie Foundation. https://www.charliefoundation.org/. Accessed 6 October 2017.
  7. Kossoff, E.H., et al. "Optimal Clinical Management of Children Receiving the Ketogenic Diet: Recommendations of the International Ketogenic Diet Study Group." Epilepsia. 2009 Feb;50(2):304-17.
  8. Hosain, S.A., et al. "Ketogenic Diet in Pediatric Epilepsy Patients With Gastrostomy Feeding." Pediatr Neurol 2005;32:81-83.

About the Author

Eric H. Kossoff, MD, is director, Child Neurology Residency Program, Professor of Neurology and Pediatrics, and medical director of the Ketogenic Diet Center at the Johns Hopkins Medical Institutions. He may be contacted at ekossoff@jhmi.edu.

Cite as: Kossoff, E.H. "Intractable Epilepsy and the Value of Formulated Ketogenic Diet Products." Regulatory Focus. October 2017. Regulatory Affairs Professionals Society.


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