Does a Regulatory Pathway for Cannabis-Derived Prescription Pharmaceuticals Exist in the US?

All new prescription drugs introduced to the US market must be evaluated by a “tried and true” regulatory approval process established by the Federal Food, Drug, and Cosmetic (FDC) Act of 1938 (1).  The United States Food and Drug Administration (FDA) is the federal agency that oversees new prescription drug approvals.  Of course, over the years, changes have been made to the approval process to accommodate the scientific, medical and technology advances that have been made in the biotechnology, pharmaceutical and medical devices industries.

While the approval process is somewhat arcane and difficult to navigate at times, the end result is always the same. That is, approved drugs are biochemically uniform, stable, safe and effective.  Further, new drugs must posses a practical and suitable delivery system and be manufactured according to current Good Manufacturing Practices (CGMP; 2)

And, probably surprising to some, the same pathway that is used to approve new pharmaceutical and biotechnology drugs can be used to garner regulatory approval for cannabis-based  prescription drugs.  At present there are several cannabis companies, most notably, GW Pharma, that are using the pathway to get approval for their products.  However, the progress of these approvals has been greatly slowed by the fact that cannabis is federally scheduled as a Schedule 1 drug and is illegal (3). Sadly, this adds another layer of complexity to the federally-mandated regulatory approval process.

To overcome this wrinkle, 27 states including the District of Columbia (DC) have made medical marijuana legal (4).  This means that medical marijuana products sold to the public in states where it is legal do not have to go through the rigorous regulatory approval process to assure drug uniformity, quality, efficacy and safety.  Put simply, there is no regulatory oversight and the quality, safety and effectiveness of medicinal cannabis products cannot be confirmed nor guaranteed.  Ironically, this is the environment that led to the approval of the 1938 Federal Food Drug and Cosmetic Act to ensure that prescription drugs are safe and effective.

The best solution to this conundrum is to reschedule cannabis so that it is no longer illegal at the federal level. This will require medical cannabis companies to follow the new prescription drug regulatory process (that ensures product quality, efficacy and safety) before their products can be sold to US consumers.  While this may increase the time  for medical cannabis products to hit the market, it will guarantee the safety and therapeutic benefits of cannabis products for patients who suffer from diseases that cannot be controlled by conventional prescription drugs.

References 

  1. https://www.fda.gov/AboutFDA/WhatWeDo/History/Milestones/ucm128305.htm Accessed August 24, 2017
  2. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211 Accessed August 24, 2017
  3. https://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm498077.pdf  Accessed August 24, 2017
  4. https://en.wikipedia.org/wiki/Medical_cannabis_in_the_United_States  Accessed August 24, 2017

THC, CBD and Multiple Sclerosis

The established immunomodulatory properties of certain cannabinoids, most notably Δ-9 tetrahydrocannabinol (THC)  and cannabidiol (CBD), suggested that they may be therapeutically useful to treat multiple sclerosis (MS) which is generally believed to be autoimmune neurological diseases. (1). To that point, from 2005-2009, clinical trials involving 1300 patients were conducted to assess the effects of Cannabis, cannabis extracts and synthetic THC on MS and MS-related muscle spasticity and pain. (2, 3).

The results of these studies showed that cannabis extracts containing different ratios of THC and CBD as well as THC and nabilone (synthetic THC) can improve MS-related symptoms of spasticity, pain and urinary incontinence.  (2, 3 ) Additional clinical studies led to the approval of GW Pharma’s Sativex® (1:1 ratio of THC: CBD) in 27 countries (not the US) as a treatment for MS spasticity (4).

At present, in the US, there are 15 late stage clinical trials in progress that are evaluating smoked/vaporized cannabis (2) and Sativex® (13) as treatments for MS and MS-related spasticity, pain and urinary incontinence (Table 1).

Based on GW Pharma’s success with Sativex® as a treatment for various MS indications in other countries, it is likely the company will receive approval as an MS treatment in the US.

 References

  1. Giacoppo S, Mandolino G, Galuppo M, Bramanti P, Mazzon E. Cannabinoids: new promising agents in the treatment of neurological diseases. Molecules 2014; 19:18781-18816
  2. Zajicek JP, Apostu VI. Role of cannabinoids in multiple sclerosis. CNS Drugs 2011; 25:187-201
  3. Hazenkamp A GF. (2010) Review on clinical studies with cannabis and cannabinoids 2005-2009. Cannabinoids 5(special issue) 2010; 1-21.
  4. Zajicek JP, Hobart JC, Slade A, Barnes D, Mattison PG, Group MR. (2012) Multiple sclerosis and extract of cannabis: results of the MUSEC trial. Journal of Neurology, Neurosurgery, and Psychiatry 2012; 83:1125-1132.

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.