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Regulatory Radar: FDA Close to Approving First Marijuana-Derived Drug Product
An FDA expert panel was recently called upon to review a new drug application (NDA) by GW Pharmaceuticals for its product Epidiolex® containing the purified extract cannabidiol (CBD) from the marijuana plant. GW Pharmaceuticals is seeking approval for use of Epidiolex as an adjunctive treatment of seizures associated with Lennox-Gastaut (LGS) and Dravet syndrome in patients older than 2. LGS and Dravet syndromes are rare and severe kinds of epilepsy that start in childhood, with patients suffering from severe seizures.
The approval of Epidiolex would mark the first marijuana plant-derived drug product and a first in a new class of antiepileptics. CBD, the active ingredient of Epidiolex, does not produce the high associated with marijuana, which is attributed to tetrahydrocannabinol (THC). The FDA has previously approved non-plant-derived synthetic medications that resemble or are identical to THC as contained in marijuana plants, including:
- MARINOL (initial approval in 1985) and SYNDROS (approved in 2016), both containing a synthetic form of THC (dronabinol, a pure isomer of THC, (−)-trans-Δ⁹-tetrahydrocannabinol)
- Cesamet (approved in 1985) containing the synthetic cannabinoid nabilone
These drugs, which are approved to treat nausea from chemotherapy in cancer patients and anorexia associated with weight loss in patient with AIDS, are listed at Schedule III (MARINOL) and Schedule II (SYNDROS and Cesamet). GW Pharmaceuticals also developed the drug Sativex® (nabiximols), a marijuana plant extract containing THC and CBD that is used to treat spasticity due to multiple sclerosis. It is formulated as a mouth spray and sold throughout Canada and in EU countries.
The FDA expert panel recommended Epidiolex for approval by a vote of 13-0. The review included data from three Phase 3 randomized controlled trials and an open-label extension study. In these studies Epidiolex was shown to be well tolerated, with most adverse events assessed as mild or moderate. A significant decrease in frequency of seizures was observed (44 percent of subjects receiving Epidiolex vs. 22 percent of placebo subjects) when used as an adjunctive therapy to antiepileptic drugs in patients with LGS and Dravet syndrome over a 14-week treatment period.
The reason it has taken this long for a marijuana plant-derived drug product to progress toward FDA market approval has often been attributed to the difficulty in conducting research hampered by marijuana’s designation as a Schedule I controlled substance.
Clinical research using marijuana or its purified elements in the U.S. is more complex as it involves interactions with multiple federal agencies in addition to filing an IND with the FDA. This includes sourcing as the product has to be obtained from the National Institute on Drug Abuse (NIDA) or another Drug Enforcement Administration (DEA)-registered source. To date, the main source of research-grade marijuana for scientific study is through the NIDA drug supply program which contracts with the University of Mississippi to grow marijuana for use in research studies; this includes marijuana made into cigarettes and other purified elements of marijuana at varying strengths or potencies.
Further, as a Schedule I controlled substance under the Controlled Substances Act, marijuana used in a clinical trial requires special site licensure and investigator registration by the DEA.
At present the DEA continues to classify marijuana and its extracts (including CBD) as Schedule I substances, on the basis that they have no proven medical value and a high potential for abuse. If Epidiolex is approved, the DEA will have to reschedule CBD to a less restrictive schedule given that FDA approval demonstrates a medical value.
It is now up to FDA to make its decision on Epidiolex, which is expected by the end of June (Prescription Drug User Fee Act target date of June 27, 2018). FDA expert panel decisions are not binding but are often followed by FDA. The approval of Epidiolex may open the path for others to conduct clinical studies and lead to other marijuana plant-derived products for other indications to reach the market.
Another development that would significantly reduce the barriers to clinical research with plant-derived marijuana products, if passed, is a bill by Senate Minority Leader Chuck Schumer, D-N.Y., that seeks to decriminalize marijuana on the federal level and remove marijuana from the list of scheduled substances. In addition, legislation introduced under this bill would seek to invest in public health research to better understand the effects of THC on the brain and the efficacy of medicinal marijuana for specific ailments.
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