Aaron Harding is SYNGAP1 Dad to Jaxon and shares information, data, and resources for those considering the pursuit of using Epidiolex off-label to treat seizures.
You have tried several anti-epileptic drugs (AEDs) for seizures with mixed success. You hear people talking about cannabidiol (CBD) to treat seizures, one being FDA approved Epidiolex, and the other whole-plant derived CBD. With the growing demand of CBD to treat seizures, the FDA in its role to ensure public safety states in its news release from June 2018, “We’ll continue to support rigorous scientific research on potential medical uses of marijuana-derived products and work with products developers who are interested in bringing patients safe and effective, high quality products.”
However, rigorous scientific research is expensive and slow. As a result, healthcare providers will prescribe a drug off-label based on the clinical indication of the drug in relation to their patient’s medical condition rather than wait for FDA approval for the condition they’re treating. But getting payer’s approval and getting insurance to pay for off-label drug use remains a hurdle and barrier.
Here we provide background information on Epidiolex, share what the FDA and payers say about “off label drug use,” and suggest questions to discuss with your medical providers when considering Epidiolex.
Intended Use and Seizure Type Comparison
The Epidiolex package insert states, “Epidiolex is the first and only FDA-approved prescription cannabidiol (CBD) used to treat seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in patients 1 year of age and older.” Epidiolex is an “add on” anti-epileptic drug (AED) used in addition to primary AEDs. These three Developmental and Epileptic Encephalopathy (DEE) syndromes do not have anything specific in common except that they were a part of FDA clinical trials conducted for Epidiolex. Renad Abu-Sawwa writes in Emerging Use of Epidiolex (Cannabidiol) in Epilepsy, “[P]atients with these aforementioned syndromes experience seizures that vary in subtype, severity, and frequency.”
So how does SYNGAP1-related intellectual disability compare? The seizure types that these three DEEs have in common with SYNGAP1 are presented in this table:
FDA: Off Label Drug Use (OLDU)
Off-label drug use involves “prescribing a medication for indications, or using a dose or dosage form, that have not been approved by the FDA.” The FDA does not regulate the practice of medicine by healthcare providers. There is the expectation that providers will use medical judgment to do no-harm when prescribing OLDU based on the known body of science for a medication’s indications.
Obtaining FDA approval for additional indications is costly and time-consuming. Pediatric populations are often excluded from clinical drug trials; therefore, there are often many OLDU examples. According to the Center for Medicare and Medicaid Services (CMS), a written request with supporting data from accepted compendiums, which includes publications from peer-reviewed journals, must be submitted to payers by the requesting provider. Currently, the following have been published on Epidiolex in SYNGAP1 patients, which has been shown to be clinically effective:
- Kuchenbuch M, et al. Add‐on cannabidiol significantly decreases seizures in 3 patients with SYNGAP1 developmental and epileptic encephalopathy. Epilepsia Open. 2020 Sep; 5(3): 496–500.
- Lattanzi, S., et al. Highly Purified Cannabidiol for Epilepsy Treatment: A Systematic Review of Epileptic Conditions Beyond Dravet Syndrome and Lennox–Gastaut Syndrome. CNS Drugs, Volume35, pages 265–281 (2021).
- Zhou, D., Dennis E., Snehal, I., Swaminathan, A. Cannabinoids in the Treatment of Epilepsy: A Review. EMJ. 2021; DOI/10.33590/emj/21-000951.
Insurance Payer Policy Guidance
U.S. healthcare medical interventions are outlined in payer policies, which can vary between states and each commercial and private payer. These policies determine if provider-prescribed interventions will be reimbursed. Payers’ policies for OLDU will normally align with CMS written policy.
It is not uncommon for prescribed interventions to be denied if the intervention’s use is not a part of standard of care guidelines or for drugs that would be OLDU. It is important to note, each payer has an appeals process when there is a denial, which you should discuss with your provider.
Kevin Frye, SYNGAP1 dad and a lawyer, received a payer denial when his provider wanted to prescribe Epidiolex. Kevin reviewed the payer’s medical policy and wrote a letter in response, which ultimately resulted in Epidiolex being approved.
In reviewing his applicable medical policy, Kevin was unable to locate a policy specific to Epidiolex or seizure medications generally, so it was unclear what portion of the policy provided the basis for denial. He did, however, locate a policy titled Genetic Testing for Epilepsy. The policy is intended to aide early diagnosis of genetic epilepsies in childhood, for disorders similar to and including SYNGAP1, by finding that genetic testing is medically necessary for children who present with clinically severe seizures that affect daily functioning with onset before age 5, and specifically “if positive test results may lead to changes in medication management.”
Moreover, a section of the policy included the following: “[t]he choice of medications, and the combinations of medications for patients who require treatment with more than one agent, is complex.” The policy further states that “one-third of patients are considered refractory to medications” and that “detecting genetic markers that identify patients who are likely to be refractory to the most common medications…may lead to directed treatment that will result in a more efficient process for medication selection, and potentially more effective control of symptoms.”
Kevin pointed out that there is cognitive dissonance between this policy that explicitly anticipates medication changes following a genetic diagnosis and the determination of the Medical Director to deny Epidiolex. One of the primary reasons the policy finds genetic testing medically necessary for children like ours is because of the anticipated benefits related to more targeted treatments upon diagnosis. Kevin explained that but for the SYNGAP1 diagnosis, there would not have been the information used to make the decision to pursue Epidiolex in the first place. In other words, without the SYNGAP1 diagnosis, medication decisions are made in a process akin to fumbling in the dark to discover an effective anti-convulsant. With the diagnosis, it is possible to be more selective by utilizing data and information from others with the same diagnosis.
The following are discussion points to have with your provider if you want to consider the use of Epidiolex:
- Ask if your child’s EEG/seizure type(s) supports a Lennox-Gastaut syndrome (LGS) diagnosis, as LGS is an approved indication and a clinical diagnosis given to a subset of SYNGAP1 patients.
- Are they experiencing refractory seizures? Refractory epilepsy is diagnosed after failure of adequate trials in two tolerated and appropriately chosen and used antiepileptic drugs to achieve sustained seizure freedom. There are numerous published journal articles on “Epidiolex + Refractory Seizures.” SYNGAP1 is known to be refractory.
- Have you experienced multiple AED failures? If yes, the Epidiolex information says that clinical trials “included patients who failed on several medicines. Epidiolex clinical trials included people who had typically failed on 4-6 prior anti-seizure medicines.” Many SYNGAP1 patients are on two or more AEDs.
- Does your applicable medical policy have any provisions that may be helpful, similar to the Genetic Testing for Epilepsy policy described above? If so, this language may be helpful in making the case for new treatments discovered as a result of the SYNGAP1 diagnosis.
- Furnish your provider with copies of the peer-reviewed published literature to assist with satisfying the requirement for compendium support.
Testimony from many SYNGAP1 caregivers is that Epidiolex is an effective adjunct AED based on SYNGAP1 seizure types. This is corroborated by published literature. If you desire to pursue the use of Epidiolex, you can assist your provider by providing supporting evidence of Epidiolex’s effectiveness in SYNGAP1 seizure types as outlined in this article. This, along with foreknowledge of your payer’s policy, will hopefully increase your chance for obtaining Epidiolex as an AED.