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

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

Companies Developing Cannabis-Derived Pharmaceuticals

There is a growing body of evidence that suggests that extracts containing multiple cannabinoids or a single cannabinoid can be developed as a pharmaceutical product to treat specific therapeutic indications.  There are a small number of companies that have announced their intentions in this space.  Rumor has it that many major pharmaceutical and biotechnology companies are quietly evaluating this business opportunity, but are reluctant to disclose their forays into the Cannabis space for legal and public relations reasons.

Below is a partial list of companies who are actively involved in development of Cannabis-derived pharmaceuticals.

I will update the table soon as there are lots of new startups that have entered the space in the past 6 months or so!

Company Product Properties Indication(s)
AbbVie Marinol® (dronabinol) Synthetic Δ-9-THC Chemotherapy-induced nausea/vomiting (CINV); MS neuropathic pain; HIV/AIDS appetite stimulate
Valeant Pharmaceuticals International Inc Cesamet®

(nabilone)

Synthetic Δ-9-THC Management of  nausea/vomiting
GW Pharma Sativex®

(naviximols)

Mixture of extracts of cannabis plant containing two cannabinoids in 1:1 ratio, Δ-9-THC and CBD (cannabidiol) in 50% alcoholic solution ; oro-mucosal delivery (mouth spray) Neurologic and cancer-related pain; Spasticity in patients with MS
Epidiolex® CBD (cannabidiol) liquid extract from genetically-defined cannabis strain Orphan pediatric epilepsy; Dravet Syndrome and Lennox-Gastaut syndrome
GWP42003 Not disclosed Ulcerative colitis
GWP42004 Not disclosed Type 2 diabetes
GWP42006 Cannabidivarin (CBDV) Adult epilepsy
Society for Clinical Research (Germany) Cannador® Oral capsule containing whole plant extract with standardized THC:CBD ratio of 2:1 Muscle stiffness; MS spasticity/pain; cachexia in cancer patients, post-operative pain management
Kannalife Not named Cannabis extract/semi-synthetic CBD (cannabidiol) Hepatic Encephalopathy
Aphios APH-080 Liposomal formulation of Δ-9-THC CINV; Appetite stimulant for HIV and cancer patients
APH-1305  CBG (cannabigerol) liposomal-oral delivery MS & other neuroinflammatory  neurodegenerative disorders
Cannabis Sciences CS-S/BCC-1 CBN (cannabinol) enriched extracts Oncology
CS-TATI-1 Plant extract Kaposi Sarcoma
Not Named CBN (cannabinol) plus other cannabinoids Anxiety, sleep disorders, Alzheimers disease
Medical Marijuana Sciences Not Named CBD (cannabidiol) extracts plus microencapsulation technology Brain and pancreatic cancer