Cannabis Clinical Investigations in Colorado 2019

By Heike Newman *

Although, as of this writing, FDA has approved two cannabinoid-based medicines derived from isolated synthetics: dronabinol and nabilone, and one plant-derived pure cannabinoid, FDA has not yet approved a marketing application for a drug product containing or derived from the whole cannabis plant. Clinical investigation of cannabis-based products outside of FDA’s Commercial Investigational New Drug Approval (IND) process has proven to be problematic.1 In 2018, FDA approved Epidiolex, a plant-derived pure cannabidiol (CBD) approved as an oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients two years of age or older. FDA previously approved dronabinol, a synthetic delta-9-tetrahydrocannabinol (THC) marketed as Marinol or Syndros, to treat nausea and vomiting associated with cancer chemotherapy and loss of appetite and weight loss in people with HIV infections, and nabilone, a synthetic compound similar to THC, marketed as Cesamet, to treat nausea and vomiting associated with cancer chemotherapy. The use and possession of recreational marijuana and its components continues to be illegal under federal law, notwithstanding the approved use of medical cannabis in thirty-three states. This article focuses on the medical cannabis clinical investigation climate in Colorado and identifies several issues that should be addressed by state and federal authorities to facilitate the performance of bona fide clinical investigation of substances for which there is much credible anecdotal evidence of medicinal benefit for indications including but not limited to autism (Bar-Lev Schleider L, 2019), joint pain (Miller RJ, 2017), and dermatological conditions (Marks DH, 2018).

Introduction

In November of 2010, Colorado Amendment 20, known as the Medical Use of Marijuana Act, passed with fifty-four percent support from Colorado voters. This Amendment allows cannabis use “for persons suffering from debilitating medical conditions”, including cancer, glaucoma, human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), and treatment for cachexia; severe pain; severe nausea; seizures, including those that are characteristic of epilepsy; and persistent muscle spasms, including those that are characteristic of multiple sclerosis. The amendment allows for other medical conditions, or treatment for such conditions, to be added if approved by the state health agency. In 2017, SB 17 added Post-Traumatic Stress Disorder (PTSD) to the list of approved medical conditions, and on February 7, 2019, HB 19-1029 authorized the addition of Autism spectrum disorder to the list.

Under Colorado state law, the Colorado Department of Public Health and Environment (CDPHE) is required to maintain a registry of patients approved to carry a Medical Marijuana Registry (MMR) identification card, known as “Red Card”. Registration for a Red Card requires a state-licensed, MMR-registered physician to certify that the patient suffers from one of the approved medical conditions that allow medical cannabis use.

In November 2012, Colorado Amendment 64 passed statewide by approximately fifty-five percent, making Colorado the first state to legalize the recreational use of cannabis. This amendment allows adults aged twenty-one or older to grow cannabis plants privately in a locked space and to purchase cannabis from a state-licensed source.

Compared to medical cannabis users, recreational cannabis users are restricted to a lesser number of homegrown cannabis plants, are limited in the quantity of useable product that can be purchased, and incur a higher cost when purchasing cannabis products; medical cannabis is sold without excise, state, and local tax, which currently adds twenty-eight percent to the price of the recreational product.

In February 2015, CDPHE approved funding for the first two clinical investigations with cannabis at the University of Colorado on the Anschutz Medical Campus (CU), pending FDA and DEA approvals and with limitations on which products could be used.

In 2018, Colorado became one of eight states with a medical cannabis research program.2 Colorado HB17-1367, effective July 1, 2018, authorizes cannabis clinical investigations and permits licenses that allow the holder to either possess cannabis for research purposes, or to grow, cultivate, possess, and transfer cannabis for research purposes within Colorado, effectively expanding the choice of products that may be used in clinical investigation.

However, despite these allowances, clinical investigators at the University of Colorado continue to have many restrictions for conducting clinical investigations with cannabis products because CU is required to comply with federal laws, regardless of state allowances. Part of CU’s commitment to Human Subject Protection is its compliance with applicable federal and state laws, regulations, and requirements documented in its Federalwide Assurance (FWA)3 for the Protection of Human Subjects, which is filed with the Department of Health & Human Services’ (HHS) Office for Human Research Protection (Department of Health and Human Services, 2019).

Federal law requires that cannabis used for clinical investigations be obtained through the National Institute on Drug Abuse (NIDA), under an Investigational New Drug (IND) application from FDA as well as a Drug Enforcement Administration (DEA) Schedule I license. The Controlled Substances Act (CSA) created five Schedules (classifications) with varying qualifications for substances included in each. Substances in Schedule I have no currently accepted medical use in the United States, a lack of accepted safety for use under medical supervision, and a high potential for abuse. No prescription may be written for Schedule I substances, and the substances are subject to production quotas imposed by DEA. Ethical oversight over investigations with cannabis must be provided through an Institutional Review Board (IRB) registered with HHS.

Due to the above sourcing requirements, investigations on products available at Colorado’s medical and recreational dispensaries are limited to observational studies, such as surveys or patient registries, and can be conducted to evaluate parameters including product preferences, patient use patterns, or patient-reported benefits. Because observational studies cannot require standardized product administration, or use of a specific cannabis product, these studies are of little use in assisting with the development of dosing instructions, exposing dose-dependent effects, providing objective data on clinical efficacy, or identifying potential interactions with foods or other drugs or pharmaceutical compounds.

The following sections describe additional challenges that CU clinical investigators are confronted with when considering clinical investigations with cannabis products.

Products for Clinical Cannabis Investigations in the United States

Currently, the sourcing of cannabis needed for research is limited to one supplier, NIDA. Under the 1961 Single Convention on Narcotic Drugs (United Nations, 2018), cannabis is classified as a DEA Schedule I controlled substance and requires DEA oversight and regulation of the cultivation of cannabis for investigational purposes. Since 1968, DEA has issued only one license for this cultivation, which is with the University of Mississippi (UM). NIDA’s contract with UM was renewed in 2015 (NIDA, 2018).

Cannabis for clinical investigations cannot be sourced locally and must be obtained through NIDA’s Drug Supply Program (DSP). All cannabis for the DSP is restricted to be sourced through contract with UM. UM’s capability to provide pharmaceutical-grade cannabis to NIDA’s DSP may have contributed to its extension of the contract since 1968, but an increasing number of companies in the maturing U.S. cannabis industry are implementing industry-specific good manufacturing practices (GMPs) and standards to distinguish their products and are increasing the quality of cannabis products available for research.

Clinical investigators also have the option to use commercially available products such as Marinol (dronabinol capsules, synthetic THC), Syndros (dronabinol oral solution, synthetic THC), Cesamet (nabilone capsules, synthetic THC), or Epidiolex (oral solution, plant-derived pure CBD); or products currently under an active commercial IND application filed with FDA by a pharmaceutical sponsor. THC, or delta-9-tetrahydrocannabinol, is one of the cannabinoids naturally occurring in the Cannabis plant and is the principal psychoactive constituent of cannabis. CBD, or cannabidiol, is one of the over 100 known cannabinoids of the Cannabis plant; however, CBD does not cause the intoxication or euphoria (the “high”) that is observed with THC.

These limited product options are insufficient because they do not cover the spectrum of cannabinoid profiles or formulations clinical investigators desire to study for the purpose of determining cannabis’s effects in the broad range of patient populations that could potentially benefit. For instance, the only pure CBD currently available is Epidiolex, which is provided as an oral solution. But investigators are also looking for pure CBD in powder form to investigate, for example, the effects of inhaled CBD on the respiratory system, as well as to incorporate into topical products to study its effects on those with certain dermal conditions.

Despite the passing of the 2018 Farm Bill, the current uncertainty about FDA and DEA’s stand on clinical investigations with hemp and hemp-derived extracts, including CBD, has stalled proposals for the pursuit of low THC formulations in clinical investigations at CU.

Also, and unfortunately, pure cannabinoids other than CBD and THC are not currently available in any formulation. Given that CBD and THC are only two of many cannabinoids in Cannabis plants, this creates another gap for clinical investigations.

The only products that currently combine CBD and THC are bulk cannabis, cannabis cigarettes, and a 30:1 whole-plant extract suitable for oral administration, again only available from NIDA. More cannabinoid ratios and cannabinoid combinations are needed and would be of great value for comparative studies.

Further, formulations for more discreet and user-friendly self-administration channels, such as vape liquids, sublingual capsules, or tinctures, are not available but would maximize study participants’ compliance with the investigation’s treatment regimen. These formulations could also increase study participation in patients with impaired mobility, patients who decline to smoke a cannabis product, or patients with co-existing health conditions where smoking is contraindicated.

Studying a product currently being investigated under an industry-sponsored IND may appear to be one solution to a clinical investigator’s search for a suitable cannabis source for his or her study, but unfortunately, the investigator remains at risk of losing access to the study product at the pharmaceutical sponsor’s discretion. This was the case for one CDPHE-funded study at CU when a pharmaceutical sponsor denied further access to the investigational product, which required a switch in sourcing that caused a delay of the ongoing investigation of more than twelve months.

Quality Concerns Associated with NIDA Cannabis Products

In early 2017, a researcher in Arizona, Dr. Susan Sisley, reported that an independent laboratory found mold in some samples of bulk cannabis she had received from NIDA, but she proceeded with the investigation because the counts were below those considered hazardous (PBS, 2017). There is currently no universally accepted standard for levels of mold in cannabis, and the existing limits currently set by different health organizations range from 500 to 200,000 colony forming units per gram (CFU/g). This requires that investigators obtaining cannabis from NIDA consult their state-specific law to make a decision on its acceptability and safety before administering the investigational product to study participants. The limitations in sourcing investigational product may force an investigator to switch to a NIDA product with a cannabinoid profile different from what was originally planned or may result in putting the investigation on hold until a more suitable product becomes available. Since April of 2018, NIDA has been conferring with FDA to determine what analyses and specifications are appropriate for NIDA-supplied cannabis, but no announcements have been made as of the writing of this article.

Since 2017, NIDA provides Certificates of Analysis (CoAs) for their cannabis which indicate product storage in freezers for up to ten years prior to shipment. Investigators are appropriately concerned about using products that have been stored for several years and question whether results from clinical investigations with these products can be correlated with fresh cannabis products. A side-by-side comparison of NIDA products frozen long-term against equivalent fresh products in a clinical investigation has, to our knowledge, not yet been conducted, but would be helpful to address this concern.

Outdated CoA test results have also been expressed as a concern by investigators. Although NIDA has committed to re-testing its product every few years, it remains unclear whether samples are also routinely re-tested immediately prior to shipment. If not currently performed, this would be another recommendation for improvement to sourcing these products.

NIDA Products’ Lower THC Potency Is Not Representative of Local Cannabis Products

Cannabis products sourced from NIDA’s Drug Supply Program have demonstrated lower THC potency in comparison to products available in local Colorado dispensaries. While NIDA’s DSP makes available cannabis with THC levels above ten percent (NIDA, 2019) in Colorado from local dispensaries, investigators can source cannabis with THC levels close to thirty percent; these differences can contribute to data extrapolation limitations.

The need for a wider range of research cannabis has been discussed for several years. In July 2016, NIDA solicited information related to increased varieties of cannabis and cannabis products for research through a Request for Information (RFI) (NIH, 2016). Results of the RFI were published in November 2016 (NIDA, 2018), and the responses covered the range of issues described above, such as strains and products that reflect what is available in state dispensaries, increased THC potency, increased number and variety of cannabinoids, different formulations, and several researchers also recommended that cannabis products developed under FDA current Good Manufacturing Practices (cGMP) be made available.

In August 2016, DEA announced a policy change designed to increase the number of entities registered under the Controlled Substance Act to grow (manufacture) cannabis that can supply products to legitimate researchers in the United States (FR Doc 2016-17955). By mid-2017, at least twenty-five cannabis growers had submitted their manufacturing applications to DEA. Hopes were high among the clinical investigators, but sadly, to date, none of the applicants have been approved, and DEA has not provided an explanation for the delay, requested additional information, or announced an anticipated date of approval for those operations.

DEA approval for additional cGMP-compliant suppliers within the United States would solve many of the current gaps in available investigational products and formulations, and this could be supplemented as needed with approval for imported formulations and active pharmaceutical ingredients (API), all of which could be added to NIDA’s product catalog for use in human studies.

However, in addition to cGMP compliance for the manufacturing of formulations and APIs, additional standards would need to be developed to bring cannabis growers and product manufacturers in line with FDA requirements of a Research IND. This, in turn, would improve overall cannabis product quality. For instance, standardizing acceptable levels of microbial contaminants, such as mold, for all types of cannabis products and formulations would help reduce ambiguity and differences in the interpretation of test results. Standardizing the methods used to grow, harvest, sample, process, and analyze cannabis and derived products would provide consistency in the quality of product across DEA-approved sources, including new sources yet to be identified. Further, confidence in the investigational products would be enhanced if standards for the duration of and requirements for the storage of cannabis and formulations were set. Discussions around the need to develop standard procedures for the cannabis industry remain ongoing in Colorado. A summary of proposed standards was recently made available by a local company (Medpharm Holdings 2019, http://www.medpharmholdings.com/) and is provided in Apendix A of this article.

Funding Cannabis Clinical Investigations

Due to cannabis’s illegal status on the federal level, investigators at CU cannot accept research funding from entities directly involved in the cannabis industry, as this may be considered the receipt of money from illegal business activities under the federal Racketeer Influenced and Corruption Organization Act (RICO).

In general, federal funding for therapeutic cannabinoid research is low. In 2017 and 2018, therapeutic cannabinoid research (mostly in-vitro, rodent, or non-human primate research, not placebo-controlled clinical trials) 4 received approximately $37 million annually in NIH grant funding; this is only a small fraction of the approximate $300 million annually in funding approved for tobacco research (NIH, 2018). As a result, CU’s clinical Investigators are forced to rely on competitive research grants awarded by CDPHE. Since 2015, CDPHE has awarded a total of $11.7 million dollars for medical research,5 which provided funding for four clinical investigations at CU, two of which are still ongoing and two have not yet started.

More research funding is needed for progress to be made in the investigation of cannabis-based products. Sources of funding could be expanded upon if donations were managed through a clearinghouse or special funds distributor system to oversee the distribution of funds submitted for clinical investigations. For Colorado, CDPHE is uniquely positioned to explore this option. In 2014, Colorado Senate Bill SB 14-155 authorized the creation of the Medical Marijuana Research Grant Program. SB 14-155 specifies that “Program grants will be paid from the Health Research Subaccount in the Medical Marijuana Program” and that the “grant program may solicit, apply for, and accept money from foundations, private individuals, and all other funding sources”. SB 14-155 also states that “all donors shall be advised that moneys given for purposes of this section will be used to study both the possible medical benefits and detriments of marijuana and its component parts and that he or she will have no control over the use of these moneys.” To date, CDPHE has not yet explored the implementation of this legislation.

Alternatively, an independent national entity could also function as a clearinghouse similar to CDPHE as outlined above.

Other Hurdles

The illegal status of cannabis on a federal level prompted Colorado’s State Board of Pharmacy to object to the use of licensed pharmacies in the management of cannabis, even for investigations under IND with FDA and with DEA Schedule I Research license. The Colorado DEA field office will not approve storage of research cannabis products in a state-licensed pharmacy because of its Schedule I classification. As a consequence, CU investigators cannot utilize the existing licensed investigational drug pharmacy on its campus to manage cannabis products for federally approved clinical investigations, even though this pharmacy is licensed, equipped, and staffed to manage controlled substances (CS-II-V). Instead, a specifically designated space had to be created to allow for the storage of cannabis products at both room and freezer temperature and for the required segregation of active (Schedule I) from placebo products. Local DEA officers inspect the storage setup for each study prior to recommending issuance of the Research license. The requirements for investigators to get to that point were not covered through the research grants and had to be funded otherwise. Research cannabis is now managed through the research teams, which includes pharmacists from the University of Colorado School of Pharmacy and Pharmaceutical Sciences.

Additional remodeling was required for the administration of research cannabis at the CU research facility. The first CDPHE-funded clinical Investigation at CU involved the use of a cannabis product containing both CBD and THC. There was (and still is) neither a commercially available product nor a product under Commercial IND that matches this profile. NIDA had products that match this profile, but they were only available as bulk cannabis or cannabis cigarettes. Since smoking and the use of open fires are not allowed within the CU research facility, cannabis cigarettes cannot be used in clinical investigations. Vaporization of cannabis, i.e. via Storz & Bickel’s Volcano Vaporizer, is acceptable since this method does not require a flame and cannabis vapors are contained within a disposable bag equipped with a valve that the participant controls for self-administration.

To accommodate this Investigation, one room was designated for vaporizer use, and the room’s HVAC system was remodeled such that the room’s air is managed independent of the building’s air. A high-efficiency HVAC system that completely exchanges the room air within two minutes was installed to ensure minimum exposure to cannabis vapor for research staff entering the room post-administration and for other participants. Remodeling costs, again, were not covered through the awarded research grant.

In September 2017, NIDA made a cannabis whole-plant extract with a 30:1 CBD:THC ratio available to investigators that requires additional processing by the research team to create the final formulation; matching placebo also are required. For the clinical investigation at CU, final formulations are dispensed to study participants for self-administration at home. FDA requires stability/product identity and sterility testing of both the active and placebo formulations to be performed using methods established by the United States Pharmacopeia (USP). DEA furthermore requires that the testing laboratory used holds a DEA Schedule I Manufacturer license. Currently, there is no listing of laboratories that meet both requirements. FDA refers all investigators to only one laboratory, which puts investigators in a vulnerable position with a sole source provider for testing necessary for investigations to commence. All of the foregoing costs, including additional costs for preparation of final formulations by a licensed pharmacist, are important considerations and should be included in proposed budgets when applying for research grants.

Permitted processing of NIDA products also remains unclear. It is unknown exactly what processing is permitted under a Schedule I Research license and what specifically would be required to be provided in the Chemistry, Manufacturing, and Controls (CMC) section of a Research IND application. These gaps in information are becoming more relevant with each new research proposal because investigators want to provide the investigational products through formulations that are relevant to the investigation and also safe and user-friendly for participants so as to maximize protocol compliance. Recent clinical investigation proposals are looking to address the use of cannabis products for various acute and chronic conditions including dermal diseases, Autism spectrum disorder, muscular sclerosis, epilepsy, and cancer. The current limitations on the availability of cannabis research materials cause difficulty since it requires investigators to extract and manipulate specific components to create their desired formulations for study. An additional limitation is that the current codified regulations do not provide clear answers about what a clinical investigator can “manufacture” under a Research license, or what kind of compounding, processing, or extracting would be permitted.6 Specific and definite guidance from DEA is needed.

Our experience to date suggests that clinical investigators studying cannabis substances would greatly benefit from FDA guidance. Based on review feedback we previously received from FDA, investigators may find it beneficial to consider including some or all of the following in their Clinical Investigational Plan, and budget the investigation appropriately.

  1. Measuring orthostatic blood pressure;
  2. Excluding participants with liver disease or those taking drugs known to cause hepatoxicity;
  3. Drawing PK samples to perform a population PK analysis;
  4. Assessing for suicidality (see FDA’s 2012 Draft Guidance “Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Protocols” (FDA, 2012));
  5. Assessing potential drug/drug interactions with concomitant medications that activate/inhibit specific cytochrome p450 isoenzymes (see FDA’s 2017 Draft guidance “Clinical Drug Interaction Studies—Study Design, Data Analysis, and Clinical Implications” (FDA, 2017));
  6. Monitoring for elevations of hepatic transaminases (see FDA’s 2009 Guidance on Drug-Induced Liver Injury (DILI) (FDA, 2009));
  7. Monitoring for abuse potential (see FDA’s 2017 guidance “Assessment of Abuse Potential of Drugs” (FDA, 2017));
  8. Monitoring for possible cases of abuse (e.g., participants taking the drug for non-therapeutic purposes, e.g., for psychoactive effects such as high or euphoria) and drug accountability discrepancies (e.g., missing medication, loss of drug, or non-compliance cases in which more investigational drug was used, as compared to expected use); and
  9. Monitoring for any potential cannabis-related withdrawal symptoms for a minimum of one week following study conclusion.

Although cannabis for medicinal use is legal in some form in over thirty states, it remains illegal on the federal level as well as classified as a Schedule I drug, having “a high potential for abuse”, “a lack of accepted safety for use under medical supervision,” and ‘‘no currently accepted medical use.” In 2016, DEA published their denial of the petition to reschedule cannabis (81 FR 53688), stating reasons such as HHS’s evaluation that there are no adequate and well-controlled studies providing efficacy, that the drug is not accepted by qualified experts, that the scientific evidence is not widely available, and that the known risks of cannabis use have not been shown to be outweighed by specific benefits in well-controlled clinical trials that scientifically evaluate safety and efficacy. Reality in 2019 is that cannabis’s illegal status and the multitude of hurdles this creates for clinical investigators make it nearly impossible to design, budget, obtain funding, or even just have access to a suitable cannabis product for scientifically sound clinical investigations to assess cannabis’s medicinal effects in various patient populations—even in states that have clearly identified the need for cannabis research under a state-authorized medical cannabis research program.

So that clinical investigators may conduct investigations with materials of high quality and there is the consistent manufacture of products that meet the needs of their study populations without risk of becoming subject to sanctions, harmonized rules, regulations, and guidelines are needed from state legislatures, DEA, FDA, and Congress.

 

Appendix A

Summary of Proposed Standard Procedures for the Cannabis Industry (provided with permission from MedPharm Holdings 2019, http://www.medpharmholdings.com/)

 

  1. Cultivation
    1. Good Agricultural Practices (GAP) for medicinal plants
      1. Pest management strategies
        1. Pesticide application
        2. Building controls and filtration
      2. Pesticide use mitigation
        1. Use of beneficial insects rather than chemical agents
        2. Prevention of contamination and cross-contaminations, reducing the need for pesticides
      3. Facility design
        1. Breezeways (no direct access to grow rooms from the outside)
        2. Secured doors to prevent unauthorized access and potential contamination
        3. Securing fertilizers, pesticides, additives to prevent unauthorized use or contamination
      4. Worker health and safety considerations
        1. Pesticide applicators permits
        2. MSDSs on site
        3. Appropriate training
        4. Emergency eyewash
        5. Allergen awareness
      5. Hygiene
        1. No uncovered street clothes in grow rooms
        2. Scrubs/lab coats/smocks provided by company with regular laundering
        3. No access to grow rooms after visiting another cannabis company’s grow site
      6. Collection practices
        1. Harvesting plants without contaminating them
        2. Proper treatment and storage of harvested plants
  2.  Processing
    1. Good Manufacturing Practices (GMP)
      1. Standards drawn from SOPs for Medicinal Products, Herbal Products, Food Products
      2. Ingredient control (authorized suppliers, inspection upon arrival, proper storage conditions, etc.)
      3. SOPs and document control
      4. Regular cleaning and documentation
      5. Documentation of all formulations
      6. Tracking all ingredients and products
      7. Prevention of contamination
      8. Appropriate ingredient and product storage conditions
      9. Pest management (i.e. non-baited traps in interior, baited traps around exterior only, insect count lights, etc.)
      10. Procedures for working with potential allergens and preventing cross-contamination with non-allergen containing products and ingredients
      11. Employee training
        1. Specific processes and formulations
        2. Specific equipment
        3. Safety training
        4. Allergen training
    2. Facility design
      1. Easy to clean surfaces
        1. E.g. stainless steel or phenolic resin
        2. Food-grade welds on stainless steel tables
      2. Ventilation
        1. Appropriate for the work area
        2. g. more ventilation where flammable solvents will be used
      3. Worker health and safety considerations
        1. Emergency shower
        2. Emergency eyewashes
        3. Access to MSDSs and SOPs
        4. Safety training
    3.  Hygiene
      1. Employees must wash hands at appropriate times
      2. Employees must maintain personal hygiene and appearance
      3. No torn or soiled clothes allowed in production areas
      4. Must wear protective covering during production (e.g. lab coat, hairnet, beard net, disposable gloves, etc.)
  3. Quality Assurance Testing
    1. Fields of Testing:
      1. Potency (cannabinoids)
        1. Must include both acidic and neutral forms of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)
          1. Tetrahydrocannabinolic acid (THCA-A, often called THC-Acid) and cannabidiolic acid (CBDA, often called CBD-Acid) are the compounds actually made by the plant Cannabis sativa. The popularly known compounds, THC and CBD, are actually breakdown products of THCA-A and CBDA.  Thus it is very important to be able to tell the difference between the two during analysis, especially when it comes to edible products.  THCA-A does not produce a psychoactive or euphoric effect when ingested, whereas THC does.
        2. Ideally includes a number of minor cannabinoids of popular interest:
          1. Cannabichromene (CBC)
          2. Cannabigerol (CBG)
          3. Cannabigerolic acid (CBGA)
          4. Cannabinol (CBN, further breakdown product of THC, can indicate how old a sample is)
          5. Tetrahydrocannabivarin (THCv)
          6. Delta-8-tetrahydrocannbinol (d-8 THC, isomer of THC, can be formed through excessive heating of cannabis extracts)
          7. Typically measured by HPLC-UV
      2. Terpene content
        1. Terpenes are thought to contribute to or modify the therapeutic effects of the cannabinoids.
          1. Terpenes are found in nearly every flowering plant in the world
          2. Many cannabis terpenes are found naturally in other plants e.g.:
                1. Pinene – Commonly found in pine trees
                2. Limonene – The primary constituent of orange and lemon peel essential oil
                3. Linalool – The primary terpene found in lavender plants
                4. Many more!
        2. Typically measured by GC-FID or GC-MS
      3. Microbial contamination
            1. Pathogenic E. coli
              1. Commonly found in soils and some fertilizers. Improper cultivation practices can contaminate the flowers of the plant.
            2. Pathogenic Salmonella
              1. Commonly found in soils and some fertilizers. Usually found as a result of some kind of infestation (birds, lizards).
            3. Total Yeast and Mold
              1. Naturally occurring yeasts and molds that infect cannabis typically do not represent a threat to human health.
                1. There are exceptions to this, and immunocompromised patients are at increased risk
              2. Excessively high levels of yeast and mold decrease product quality
              3. Excessively high levels of yeast and mold indicate an increased risk of the present of a human pathogen or toxin-creating mold species (e.g. mycotoxin producing molds)
            4. Microbial contamination can be determined by traditional plating methods or by more modern qPCR methods.
      4.  Mycotoxins
        1. Some molds produce toxic compounds called mycotoxins. These can cause acute illness in high enough doses, or they may cause cancer when exposed to smaller doses over longer periods of time.
            1. Aflatoxins
            2. Ochratoxins
        2. There are several methods for measuring mycotoxin contamination in cannabis samples. These include:  HPLC-Derivitization-Fluorescence, ELISA, and HPLC-MS/MS
      5. Heavy Metals
        1. Heavy metal contamination can come from several sources:
            1. Unapproved or contaminated pesticides
            2. Unapproved or contaminated fertilizers
            3. Contaminated soil
            4. There is a particular susceptibility to heavy metal contamination for outdoor grown cannabis because the taproot of the plant can reach depths of 10 feet or more. Heavy metals in the soil at this level can be taken up into the plant.
        2. The American Herbal Pharmacopeia has set limits for the following metals in cannabis:
          1. Chromium
          2. Lead
          3. Arsenic
          4. Mercury
        3. Other heavy metals may also be of concern
        4. Heavy metal testing is required in Colorado starting in July 2019
        5. Typically measured by ICP-AES, ICP-OES, or ICP-MS
      6.  Pesticides
        1. Pesticides are routinely applied to most edible and other crops in the country. In the case of food crops, the pesticides that are allowed to be applied to a given crop have been well studied to ensure that the pesticide will not harm human health when consumed.  Some of these pesticides may not be suitable for cannabis.  For example, the pesticide myclobutanil is routinely applied to strawberries, and residual levels are not dangerous when eaten.  However, upon heating, myclobutanil release hydrogen cyanide, a poison.  This is clearly inappropriate for use on a product intended to be heated and inhaled.
        2. Allowed Pesticides
          1. These are pesticides that have been approved by the State of Colorado for use on cannabis crops. Each label must be individually approved prior to use in the Colorado closed-loop system.  There is limited information about how appropriate it is to use these pesticides on cannabis, but many pesticides that are obviously incompatible are banned from use.
          2. Safe limits for some approved pesticides have been set in Colorado and 3rd party testing laboratories are required to test for those.
        3. Banned pesticides
          1. Any pesticide that has not been approved for use in Colorado is banned by default.
          2. Certain banned pesticides are especially dangerous or otherwise of interest to the State of Colorado. 3rd party testing laboratories are required to test for these pesticides.
        4. Pesticides are typically measured by HPLC-MS/MS and/or GC-MS/MS
      7. Water content
        1. Freshly harvested plants typically contain about 80 % moisture. This must be dried down in order to prevent mold from growing.  Depending on the climate, the final moisture content of the plant is generally between 7 and 15 %.  Moisture contents above 15 % indicates that the flower is not ready for smoking.  Originally, moisture content was used as a proxy for water activity (next section).  Higher moisture contents correlate to higher water activities.  The higher the water activity, the more susceptible cannabis is to mold and other microbial growth.
        2. This metric may not be made completely obsolete by water activity measurements. For example, most cannabinoid potencies are reported on the basis of dry-weight flower.  High moisture contents make the dry-weight potency measure less meaningful.
        3. A moisture balance can be used to determine moisture content. Alternatively, mass loss through a drying oven can be measured and reported.
      8. Water activity
        1. Water activity is a better metric to use than moisture content when evaluating the susceptibility of a substrate to microbial growth.
        2. The higher the water activity, the more susceptible a substrate is to mold growth.
        3. Cannabis will ideally have a water activity below 0.65
        4. Measured with a water activity meter
    2.  Accountability
      1. There is an unfortunate history of laboratory shopping and even laboratories cheating in order to win and retain customers. This is particularly well-documented in Washington State.  At least two laboratories in Washington State have had their certifications for testing cannabis revoked because of falsifying results.  Thus, there is a need for a robust accountability system in order to prevent things like this from happening again.
      2. Proficiency Testing (PT) is one method by which cannabis laboratories can be held accountable. Proficiency Testing involves the preparation of a sample with a known cannabinoid potency or level of contamination and providing that to the laboratory.  The laboratory must then follow their SOPs for sample preparation, analysis, and data reporting when analyzing the sample.  This result is reported to the company administering the PT, which then assigns a pass or fail grade to the laboratory for that given test.
        1. Accountability across the nation requires the ability to ship cannabis over state lines to ensure that quality assurance laboratories across the country are producing consistent results
        2. Sample needs to be blinded such that the laboratory does not know it is a proficiency test sample so they cannot circumvent testing requirements
  4.  Transportation
    1. Food safety (products needing refrigeration)
    2. Product quality concerns
    3. Security and traceability
  5.  Traceability
    1. Seed-to-sale tracking of all cannabis and cannabis products
      1. In Colorado, all cannabis, cannabis products, and cannabis wastes are recorded in the state’s Traceability system. This is primarily to prevent diversion of cannabis to the black market, but it also assists the cannabis business in inventory management and tracking every storefront that their product has gone to.
  6.  Safety/Security
    1. Locking safe for cash businesses
    2. Surveillance/Security cameras throughout the facility
    3. Secure outside doors
    4. Key-badges for entry to all doors inside and outside the facility
      1. Can prevent employees from entering areas they are not authorized to be in
      2. Can prevent employees from accessing the building outside of business hours
      3. Provides layers of security should a break-in ever occur

 

*Disclaimer: The views and opinions expressed in this article are those of the author and do not necessarily reflect the position of the University of Colorado, or of any agency of the State of Colorado, or the U.S. Federal Government.

1.  FDA allows for application for either a Commercial or Research IND. A “Commercial IND” should be submitted if the product under investigation is intended to be commercialized at a later date. (21 CFR 312.320). A “Research IND” should be submitted if the product under investigation is not intended to be commercialized at a later date. Research INDs are generally sponsored by individual investigators, academic institutions, or non-profit entities.

2.  Other states are California, Connecticut, Massachusetts, Oklahoma, Oregon, Pennsylvania, and Washington.

3.  The purpose of an FWA is to ensure that “All of the Institution’s human subjects research activities, regardless of whether the research is subject to the U.S. Federal Policy for the Protection of Human Subjects (also known as the Common Rule), will be guided by a statement of principles governing the institution in the discharge of its responsibilities for protecting the rights and welfare of human subjects of research conducted at or sponsored by the institution. This statement of principles may include (a) an appropriate existing code, declaration (such as the World Medical Association’s Declaration of Helsinki), or statement of ethical principles (such as the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research of the U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research); or (b) a statement formulated by the institution itself.” An institution must have an FWA in order to receive HHS support for research involving human subjects. Each FWA must designate at least one Institutional Review Board (IRB) registered with the Office for Human Research Protections (OHRP). The FWA is also approved by OHRP for federalwide use, which means that other U.S. federal departments and agencies that have adopted the U.S. Federal Policy for the Protection of Human Subjects (also known as the Common Rule) may rely upon the FWA for the research they conduct or support.

4.   A query against clinicaltrials.gov to identify interventional studies in the United States; funded by NIH that use CBD, marijuana, or cannabis; and have not been suspended, only shows the following:

  • One study to evaluate the effects of vaporized cannabis plus dronabinol/placebo on low back pain and neuropathic pain (NCT 02460692): study is recruiting;
  • One study to evaluate the effects of vaporized marijuana for chronic pain associated with sickle cell disease (NCT 01771731): completed but no results posted; and
  • One study to evaluate the effects of vaporized cannabis on spinal cord injury pain (NCT 01555983): study completed.

5.  In 2014, $9 million to study medical effects of cannabis use was spread over nine studies (see list of studies at https://www.colorado.gov/pacific/cdphe/approved-medical-marijuana-research-grants); total grant amounts for five-year award period ranged from $450,000 to $2,156,000, which included institutional indirect costs. In 2017, $2.7 million was spread over two projects to study medical efficacy of cannabis (https://www.colorado.gov/pacific/cdphe/researchers); total grant amounts of $1.35 million were awarded to each study for a five-year award period, including institutional indirect costs.

6.  In 21 CFR § 1301.13, coincident activities allowed under a Schedule I Research license include that “[a] researcher may manufacture or import the basic class of substance or substances for which registration was issued, provided that such manufacture or import is set forth in the protocol required in § 1301.18 and to distribute such class to persons registered or authorized to conduct research with such class of substance or registered or authorized to conduct chemical analysis with controlled substances” (emphasis added). The Controlled Substances Act, 21 U.S.C. § 802(15), defines the term “manufacture” as “the production, preparation, propagation, compounding, or processing of a drug or other substance, either directly or indirectly or by extraction from substances of natural origin, or independently by means of chemical synthesis or by a combination of extraction and chemical synthesis, and includes any packaging or repackaging of such substance or labeling or relabeling of its container; except that such term does not include the preparation, compounding, packaging, or labeling of a drug or other substance in conformity with applicable State or local law by a practitioner as an incident to his administration or dispensing of such drug or substance in the course of his professional practice. The term ‘manufacturer’ means a person who manufactures a drug or other substance.”

References

0-4-287, Colorado Constitution, Article XVIII (Miscellaneous), Section 14

Bar-Lev Schleider L, M. R. (2019, Jan 17). Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy. Scientific reports, p. 200.

Department of Health and Human Services. (2019, Feb 11). Office for Human Research Protection. From Federalwide Assurance (FWA) for the Protection of Human Subjects: https://www.hhs.gov/ohrp/register-irbs-and-obtain-fwas/fwas/fwa-protection-of-human-subjecct/index.html.

FDA. (2009, Jul). Guidances. From Guidance for Industry – Drug-Induced Liver Injury: Premarketing Clinical Evaluation: https://www.fda.gov/downloads/Drugs/…/Guidances/UCM174090.pdf

FDA. (2012, Aug). Guidances. From Guidance for Industry: Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Trials: https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm315156.htm.

FDA. (2017). Guidances. From Clinical Drug Interaction Studies – Study Design, Data Analysis, and Clinical Implications: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf.

FDA. (2017, Jan). Guidances. From Assessment of Abuse Potential of Drugs: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf.

Marks DH, F. A. (2018, Nov). The Therapeutic Potential of Cannabinoids in Dermatology. Skin Therapy Letters, pp. 23(6):1-5.

Miller RJ, M. R. (2017, Sept-Oct). Is cannabis an effective treatment for joint pain? Clinical and Experimental Rheumatology, pp. Vol.35, No.5 Suppl. 107; 59.

NIDA. (2018, Nov 25). NIDA’s Role in Providing Marijuana for Research. From National Institute on Drug Abuse: www.drugabuse.gov/drugs-abuse/marijuana/nidas-role-in-providing-marijuana-research.

NIDA. (2019, May 6). NIDA Drug Supply Program (DSP). From Marijuana Plant Material Available from the NIDA Drug Supply Program: https://www.drugabuse.gov/research/research-data-measures-resources/nida-drug-supply-program/marijuana-plant-material-available-nida-drug-supply-program.

NIH. (2016, July 7). Grants. From Request for Information: Increasing the Varieties of Marijuana and Marijuana products for Research: https://grants.nih.gov/grants/guide/notice-files/not-da-16-034.html.

NIH. (2018, May 18). Research Portfolio Online Reporting Tools (RePORT). From Estimates of Funding for Various Research, Conditions, and Disease Catgories (RCDC): https://report.nih.gov/categorical_spending.aspx.

PBS. (2017, Mar 8). PBS News Hour. From Scientists say the government’s only pot farm has moldy samples—and no federal testing standards: https://www.pbs.org/newshour/nation/scientists-say-governments-pot-farm-moldy-samples-no-guidelines.

United Nations. (2018, Dec 2). Single Convention on Narcotic Drugs, 1961. From United Nations Office on Drugs and Crime: www.unodc.org/pdf/convention_1961_eng.pdf.

 

 

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July/August 2019

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