Commercializing Cannabis-Derived Pharmaceuticals: Legal and Regulatory Challenges

The current regulatory and legal landscape for cannabis and cannabis-derived products is extremely difficult and fraught with numerous challenges. For example, in the US, cannabis and products derived from it (including hemp) are federally classified as Schedule I drugs according to the US Controlled Substances Act (1). This means that cannabis and its products have been deemed to have “no currently accepted medical use in treatment in the US” (heroin and LSD are also schedule I drugs), are harmful and consequently, are illegal (2).

Not surprisingly, its Schedule 1 classification has seriously hindered cannabis research in the US and made it extremely challenging for drug companies developing cannabis-derived pharmaceutical products (3). However, over the past decade or so, 29 states including the District of Columbia have enacted legislation that permits some form of cannabis consumption for medical purposes (4). Yet, despite this, cannabis and products derived from it remain illegal at the federal level and during interstate transport (even between states where medical marijuana has been legalized) is illegal and criminally punishable (2).

The confusion regarding cannabis use at the state and federal levels has given rise to two distinct types of companies that are attempting to commercialize cannabis (and products derived from it) for medicinal purposes. The first of these are commonly referred to as medical marijuana or medical cannabis companies. Typically, products from these companies are botanical extracts or actual plant materials derived from specific cannabis strains with anecdotally-reported medicinal properties that can be topically applied, ingested, smoked or vaporized. Patients require a “prescription” (card) from a state-licensed physician to obtain medical marijuana and it can only be used in states that permit consumption of cannabis for medical purposes. It is important to note, that while a prescription is required for medical cannabis use, these products do not require human clinical testing for safety, tolerability and efficacy (like other prescription drugs) prior to their sale in states where medical marijuana is legal.

In contrast with medical marijuana companies, biopharmaceutical companies including GW Pharma, Zynerba, Insys, Kannalife, Aphios and others (Table 1) are committed to developing cannabis-derived pharmaceuticals using conventional US Food and Drug Administration regulatory approval pathways. UK-based GW Pharma is the clear leader in cannabis-derived pharmaceutical space—its flagship product Sativex®, a plant extract, has been approved as a treatment for cancer-related pain and MS spasticity in 27 countries outside the US (5).

While the business case for developing pharmaceutical cannabis-derived pharmaceuticals is a sound one, the time and cost necessary for regulatory approval will be much greater than that for commercializing medical marijuana. At present, the United State Food and Drug Administration (FDA) has signaled a willingness to review new drug applications for cannabis-based pharmaceuticals (6). However, the agency has yet to issue definitive guidance for regulatory approval of these products and to date has not approved any application for cannabis-based products (6). Nevertheless, garnering FDA regulatory approval for cannabis–derived pharmaceuticals may offer several competitive advantages over numerous medical marijuana products that currently dominate the US market.

First, the average cost per patient of Sativex® to treat MS spasticity in countries where it has been approved has been estimated to be roughly $16,000 (6). Several studies indicate  (7, 8) that the high price of Sativex® will make it unlikely to be considered cost effective by regulators in countries with government-mandated national formularies like the UK, Ireland and Australia. However, this should not be an impediment in the US market because the federal government does not set drug prices and third-party payers dictate formulary placement and set drug reimbursement rates.

Second, unlike medical marijuana (which as previously state is a Schedule 1 drug), FDA approved cannabis-based pharmaceuticals like dronabinol and nabilone have been classified or reclassified as Schedule 2 (opioids) or Schedule 3 (codeine) drugs (5, 9). Federal regulators are likely to apply the same scheduling criteria to the next generation of FDA-approved cannabis-derived pharmaceuticals like Sativex® and others. Rescheduling will effectively allow these products to compete with medical marijuana because unlike medical marijuana—which is legal in only 29 states and cannot be transported across state borders—approved cannabis-derived pharmaceuticals can be legally prescribed, sold and used in all 50 states and US territories.

Finally, and perhaps most importantly, physicians may be inclined to prescribe FDA-approved cannabis drugs as compared with medical marijuana because they have been evaluated in human clinical trials and officially deemed to be safe and effective treatments for specific therapeutic indications.. In marked contrast, medical marijuana can be prescribed and sold in states where it is legal without going through any formal drug review process. While this is unlikely to interfere with possible therapeutic benefits offered by medical cannabis questions concerning product safety, effectiveness and reproducibility about these products are likely to continue to  arise until industry best practices are implemented and standardized.

References

  1. https://www.deadiversion.usdoj.gov/21cfr/21usc/812.htm  Accessed July 17, 2017
  2. https://www.dea.gov/druginfo/ds.shtml  Accessed July 17, 2017
  3. https://www.brookings.edu/wp-content/uploads/2016/06/Ending-the-US-governments-war-on-medical-marijuana-research.pdf  Accessed July 17, 2017
  4. http://medicalmarijuana.procon.org/view.resource.php?resourceID=000881 Accessed July 17, 2017
  5. https://www.gwpharm.com/products-pipeline/sativex  Accessed July 17, 2017
  6. https://www.fda.gov/newsevents/publichealthfocus/ucm421163.htm  Accessed July 17, 2017
  7. Pharmacoeconomic NCF. Cost-effectiveness of Delta-9-tetrahydrocannabinol/cannabidiol (Sativex®) as add-on treatment, for symptom improvement in patients with moderate to severe spasticity due to MS who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy. 2014. http://www.ncpe.ie/wp-content/uploads/2013/01/Summary-v1.pdf.
  8. Lu L, Pearce H, Roome C, Shearer J, Lang IA, Stein K. Cost effectiveness of oromucosal cannabis-based medicine (Sativex(R)) for spasticity in multiple sclerosis. PharmacoEconomics. Dec 1 2012;30(12):1157-1171.
  9. https://www.deadiversion.usdoj.gov/fed_regs/rules/1998/fr1105.htm  Accessed July 17, 2017

Treating Cancer-Related Symptoms with Cannabis

In the 1970s, purified and synthetic cannabinoids were being evaluated as palliative treatments for cancer related symptoms (1). One of the earliest recognized clinical indications for cannabinoids was cancer induced nausea and vomiting (CINV) [2].

A 1988 prospective open label trial found that inhaled cannabis effectively controlled CINV in 78% of 56 cancer patients who had inadequate control of nausea and vomiting with conventional anti-emetics (3). Also, a later report that evaluated 30 trials and over 1300 participants determined that synthetic THC molecules such as nabilone and dronabinol were more effective than conventional anti-emetics in controlling acute CINV (2). This led to the early approval of dronabinol and nabilone as treatments for CINV but their use as a treatment for CINV has not been widespread (2,3)

A quick search of the clinical trials site www.clinical trials.gov revealed that there are no US clinical trials currently underway to further evaluate the use of Cannabis as a treatment for CINV.  Moreover, there are no natural Cannabis products e.g. extracts, sprays etc, on the market today that have received US Food and Drug Administration (FDA) approval as a treatment for CINV.

Inhaled Cannabis, and extracts containing THC and CBD have been clinically found to be more effective in treating cancer-related neuropathic pain than placebo (3, 4) but their effectiveness compared with conventional pain medications is uncertain (2). Yet, despite this, GW Pharma’s Sativex® (an extract that contains 1:1 ratio of Δ-9-tetrahydrocannabinol (THC) and cannabidiol [CBD]) is an approved treatment for cancer-related pain in 27 countries outside of the US (5).

There are currently 4 US clinical trials in (various phases) that are underway to determine the effects on Sativex® on advanced cancer pain and chemotherapy-induced neuropathic pain (Table 1). Regulatory experts expect Sativex® to garner FDA approval for both indications.

References

  1. Guzman M, Duarte MJ, Blazquez C, et al. A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. British Journal of Cancer 2006; 95:197-203.
  2. Tramer MR, Carroll D, Campbell FA, Reynolds DJ, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 2002; 323:16-21.
  3. Bowles DW, O’Bryant CL, Camidge DR, Jimeno A. The intersection between cannabis and cancer in the United States. Critical Reviews in Oncology/Hematology 2012; 83:1-10
  4. Notcutt W, Price M, Miller R, et al.  Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies. Anaesthesia 2004; 59:440-452.
  5. https://www.gwpharm.com/products-pipeline/sativex  Accessed July 12, 2017

 

Cannabis Extracts, Cannabinoids and Cancer Treatment

There is a growing body of evidence that cannabinoids may have anti-tumor and cancer–fighting effects (1, 2).

Numerous studies have demonstrated inhibition of tumor growth in vitro and in animal models of disease for a variety of cancers including glioblastoma, breast, prostate, thyroid, colon, skin, pancreatic, leukemia and lymphoma (3).

The exact mechanism by which cannabinoids exert their anti-tumor effects is thought to occur via suppression of proliferative cell signaling pathways, inhibition of angiogenesis (blood vessel formation) and cell migration, stimulation of apoptosis (programmed cell death) and induction of autophagy (intracellular degradation) [3, 4].  Interestingly, cannabinoid receptors CB1 and CB2 have been found in higher concentrations on tumor cells than on surrounding normal tissue for a variety of cancers (5, 6).  Also, several studies suggest that cannabinoids may selectively inhibit tumor cell growth and proliferation while sparing normal tissue (3, 7).

Although cannabinoids exhibit possible anti-tumor effects, only a single Phase 1  clinical trial that assessed the safety and efficacy of THC in 9 patients with treatment refractory glioblastoma multiforme has been published (8).

However, at present, there are only two Phase 2 clinical trials underway or completed to assess the effect of cannabis extracts on solid tumor growth (NCT02255292) and glioblastoma (NCT01812603).  Clearly, more clinical studies are necessary to determine whether or not Cannabis extracts or different cannabinoids (singly or in combination) can be used as safe and effective cancer treatments for solid tumors.

References

  1. Bowles DW, O’Bryant CL, Camidge DR, Jimeno A. (2012) The intersection between cannabis and cancer in the United States. Critical Reviews in Oncology/Hematology 83(1):1-10.
  2. Lynch ME, Campbell F. (2011) Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. British Journal of Clinical Pharmacology 72(5):735-744.
  3. Pisanti S, Malfitano AM, Grimaldi C, et al. (2009) Use of cannabinoid receptor agonists in cancer therapy as palliative and curative agents. Best Practice & Research. Clinical Endocrinology & Metabolism 23(1):117-131.
  4. Salazar M, Carracedo A, Salanueva IJ, et al. (2009) Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. The Journal of Clinical Investigation 119(5):1359-1372.
  5. Caffarel MM, Andradas C, Mira E, et al. (2010) Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition. Molecular Cancer 9:196.
  6. Qamri Z, Preet A, Nasser MW, et al. (2009) Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. Molecular Cancer Therapeutics 8(11):3117-3129.
  7. Flygare J, Sander B. (2008) The endocannabinoid system in cancer-potential therapeutic target? Seminars in cancer biology 18(3):176-189.
  8. Guzman M, Duarte MJ, Blazquez C, et al. (2006) A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. British Journal of Cancer 95(2):197-203.

Is Cannabidiol (CBD) An Effective Treatment for Epilepsy?

Stories of the ability of Cannabis  to alleviate seizures have been around for about 150 years (1).  Early randomized, placebo-controlled clinical studies conducted between 1978-1990 involving 48 patients with epilepsy found that daily treatment with 200-300 mg of cannabidiol (CBD) for up to 4 months was safe and well tolerated (2). However the small number of patients and short trial duration were not sufficient to draw any conclusions about CBD’s efficacy (1, 2)

Over the past decade, there have been reports that cannabis extracts with high concentrations of CBD may be effective anticonvulsants for children suffering from severe forms of uncontrollable epilepsy known as Dravet Syndrome and Lennox-Gastaut Syndrome (1, 3).  At present there are 9 ongoing or completed US clinical trials that evaluated the effects of CBD on epilepsy, treatment-resistant epilepsy, Dravet Syndrome (DS) and Lennox Gastaut Syndrome (LGS)

A Table that lists the ongoing clinical trials that are evaluating CBD as a treatment for epilepsy, DS, LGS and treatment-resistant forms of epilepsy can be found here.

Industry leaders in this field include GW Pharma and a relatively new entrant called INSYS Therapeutics Inc.  Of interest, in 2014, GW pharma’s Epidiolex, a liquid formulation of highly purified Cannabis-derived CBD was granted Orphan Drug Designation by the US  Food and Drug Administration (FDA ) as a treatment for Dravet and Lennox-Gastaut syndromes and other pediatric epilepsy syndromes.

More recently, a Phase 3, double blind, placebo-controlled study conducted with 120 children and young adults with Dravet syndrome and drug resistant seizures revealed that treatment with CBD (20 mg per kilogram of body weight) per day reduced the median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (4).  Further, the percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with CBD and 27% with placebo (4). The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (4).

Finally, adverse events that occurred more frequently in the CBD group as compared with the placebo group included diarrhea, vomiting, fatigue, sleepiness and abnormal liver function test results (4).

Similar results were observed in a randomized, double-blind, placebo-controlled trial CBD clinical trial conducted with 156 patients with Lennox-Gastaut Syndrome (5).

The results from these studies suggest that highly purified preparations of CBD may be effective in controlling patients who suffer from DS, LGS and other treatment resistant forms of epilepsy.  However, additional studies must be conducted with CBD with the goal of reducing the high frequency of adverse events associated with long term CBD treatment.

References

  1. Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia 2014; 55:783-786.
  2. Gloss D, Vickrey B. Cannabinoids for epilepsy. The Cochrane Database of Systematic Reviews 2014; 3:1-23
  3. Cilio MR, Thiele EA, Devinsky O. The case for assessing cannabidiol in epilepsy. Epilepsia .2014: 55:787-790.
  4. Devinsky O, Marsh E, Friedman D, Thiele E, Laux L et al. Trial of cannabidiol for drug-resistant seizures in the Dravet Syndrome. N Engl J Med 2017; 376:2011-2020
  5. Thiele, EA, Mazurkewicz-Beldzinska M, Denbadis, S, Marsh et al. Cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox-Gastaut Syndrome (LGS): Results of a multi-center, randomized double-blind placebo-controlled Trial (GWPCARE4) American Epilepsy Society Annual Meeting. 2016. ( 1423_AES_Poster_LGS_)