By Fred Gardner
To date FDA has approved intermediate-sized INDs sponsored by Orrin Devinsky, MD, at the NYU School of Medicine, and Roberta Cilio, MD, PhD, at UCSF —each set up to follow 25 patients using Epidiolex™ as a treatment for pediatric epilepsy— plus two individual INDs by Cilio. More INDs await FDA approval. [Style note: the jargon calls for dropping the word "study" after IND, just as the word "proposal" gets dropped when researchers speak of "writing a grant.”] Devinsky and Cilio both made presentations at a conference on “Cannabidiols: potential use in epilepsy and other neurological disorders,” held at NYU October 4.
GW chairman Geoffrey Guy, MD, says, “In the coming months, if the FDA is comfortable about how things are going, there will be a number of senior epileptologists in major university centers throughout the U.S., each treating a couple of dozen patients with various epilepsies.”
Each physician-sponsored, intermediate-sized IND can enroll additional patients, with FDA approval. Given the level of need and the efficiency of the concerned parents’ network, it’s possible that in the year ahead, hundreds of children with various severe forms of epilepsy will be enrolled in INDs and being treated with GW’s Epidiolex™.
GW is the British company that got government approval in 1998 to develop cannabis-based plant extracts. Their flagship product is Sativex, a highly defined extract containing an approximately 50-50 mix of CBD and THC that has been approved by regulators in the UK and more than 20 other countries for treating pain and spasticity in Multiple Sclerosis. Unlike Sativex, which is formulated for spraying under the tongue, Epidiolex™ is a viscous liquid that comes in a bottle with a syringe dropper. It consists of more than 98 percent CBD, trace quantities of some other cannabinoids, and zero THC. “Our definition of pure,” says Guy, “is no THC.” The company will provide two strengths to the physician-investigators: 25 milligrams per milliliter, and 100mg/ml.
In recent years, GW tested several CBD formulations in animals and provided small amounts to investigators who had initiated preclinical studies in various countries. Ben Whalley and colleagues at the Center for Integrative Neuroscience and Neurodynamics, University of Reading, using mouse models of epilepsy, established safety and showed that CBD and another cannabinoid, CBDV, exert anti-seizure and anti-inflammatory effects. This research came to the attention of families in the US who had loved ones with epilepsy.
The FDA’s informal so-called “compassionate” IND program that made federally-grown cannabis available to a fortunate few in the late 1970s and early ‘80s had been given structure in 1997 when Congress passed the Food and Drug Administration Modernization Act. The FDA then developed regulations covering IND studies for unapproved drugs. These were revised over the years, and in August 2009 FDA issued its “final rule” on “Expanded Access to Investigational Drugs for Treatment Use.” The summary states:
“Under the final rule, expanded access to investigational drugs for treatment use is available to individual patients, including emergencies; intermediate-size patient populations; and larger populations under a treatment protocol or treatment investigational new drug application (IND). The final rule is intended to improve access to investigational drugs for patients with serious or immediately life-threatening diseases or conditions who lack other therapeutic options and who may benefit from such therapies.”The regulations spell out criteria for INDs. The would-be investigator must submit, among other things:
“Chemistry, manufacturing, and controls information adequate to ensure proper identification, quality, purity, and strength of the investigational drug.”In other words, FDA wants to see a highly standardized, tested, Good-Manufacturing-Practices medication —which Epidiolex™ is. The herb provided by NIDA to the four surviving beneficiaries of the old informal program would not be approved as a treatment under the current FDA regs.
Another IND requirement is:
“Pharmacology and toxicology information adequate to conclude that the drug is reasonably safe at the dose and duration proposed for the treatment use.”When GW was approached by the parents of epilepsy patients in late 2012, the company already possessed extensive preclinical data —five-and-a-half years’ worth— establishing the safety of its CBD product, as well as information the FDA would require concerning its chemistry, manufacturing, controls, pharmacology, and toxicology. The company agreed to provide purified CBD and the requisite data for a single patient IND.
Soon after the first IND got underway, an extremely favorable response was reported. Your correspondent asked about the patient’s age and gender, the level of seizure reduction, and the name of the doctor providing treatment. Guy responded:
“All these patients remain anonymous and it will be the responsibility of the physician to maintain confidentiality. As a general point, all treatments are and will be for those children and some adults who remain drug-resistant despite having tried a range of standard anti-epilepsy medications. Such drug resistance may be lack of seizure control or intolerable side effects or a combination of both. The frequency of seizures will range from many tens a day to a few per week. Therefore if benefit is to be noted it becomes apparent with days or weeks.In early 2013 GW and NYU School of Medicine arranged a meeting in New York of epilepsy specialists interested in conducting clinical research with purified CBD in the United States. Encouraged by the response to CBD treatment by the initial patient, these doctors wanted to sponsor INDs at their various institutions. “We agreed to provide them with CBD so that they could treat their most needy cases,” says Guy.
“One has to be mindful that in such patients there is often an initial ‘honeymoon effect’ when changing to any new drug. What the physicians will want to see is a sustained response over many months, perhaps with withdrawal of other anti-epileptic medicines —at which time it would not be unreasonable to expect to see case reports appearing in the medical literature.”
The term “epilepsy” applies to more than 40 different seizure disorders, some with specific causes, others more general. Guy expects the physician-sponsored INDs to yield “understanding and experience in what cannabidiol does in these different children groups, what benefit we can see, and how the results can best be measured.”
The primary purpose of a physician-sponsored IND is treatment of the patient, not research regarding effectiveness. But if investigators see signals of effectiveness —say, reduced seizures in a number of patients— it might expedite FDA approval of a “Treatment IND” by GW, otherwise known as a phase 3 clinical trial.
Will doctors throughout the U.S. be called on to submit INDs on behalf of pediatric epilepsy patients whose families want access to Epidiolex™? Interested doctors should direct inquiries to GW’s Associate Medical Director at firstname.lastname@example.org. The manufacturer has an obvious interest in confirming the doctor’s expertise and assuring that patients treated with Epidiolex will be properly selected and monitored. If the would-be investigator has an affiliation with a medical center, he or she would have to get the approval of an Institutional Review. Then s/he would need to get DEA and the corresponding state agency to license their “site” (office) for dispensing of Epidiolex. They would also need to get an import license.
O’Shaughnessy’s asked Guy why GW hadn’t publicized the anti-seizure effects of CBD back in January, when the initial patient responded so favorably —leaving it to Sanjay Gupta, MD, to break the news in August. Guy replied,
“We’re in the business of developing medicines, not headlines. If we had made a big splash about the initial findings, someone in the scientific community would ask, ‘What have you got?’ And we’d say, ‘Well, we’ve got one or two children.’ That wouldn’t be enough evidence to impress them.
“We wanted to make sure that the pediatric epileptologists were comfortable with the approach being taken and that the FDA would go with it. We’ve been very busy in the US this past year, but we’ve kept our heads down. In the months ahead you’ll see a manifestation of all that work. Then it’s a matter over the next year or two of generating sufficient data of appropriate quality and scope to be able to move towards getting approval.”Guy expects the physician-sponsored INDs to yield “understanding and experience in what cannabidiol does in these different children groups, what benefit we can see, and how the results can best be measured.” According to Guy, CBD is exerting
“not just an anti-seizure effect. It’s anti-inflammatory, neuro-modulatory, and has been shown in animals to counter neonatal hypoxic ischemia [oxygen starvation during delivery] —an important problem you see after seizures in these children.If CBD turns out to be merely equal to conventional medications prescribed for epilepsy (rather than more effective), it may well be superior in terms of side effects. There is evidence that conventional anti-consulvants are detrimental to cognition and longterm development, whereas CBD is likely to prove benign.
‘You’ve got an underlying inflammatory process which is massively exaggerated by excitotoxcity after each seizure, which is setting up the next seizure in a way. It’s not enough to treat just the seizures without treating the underlying inflammatory encephalitis and the hypoxic ischemia and the damage to neuroplasticity. Children’s brains are very plastic and can usually work around issues, but if you’re having continuing seizures and continuing inflammation, that ability will be dampened. We’re hoping from the preclinical work that cannabidiol will address a number of these different issues, not just one.”