Clinical Policy Title: Botanical marijuana for medical use

Clinical Policy Title: Botanical marijuana for medical use Clinical Policy Number: 00.02.10 Effective Date: January 1, 2015 Initial Review Date: August 20, 2014 Most Recent Review Date: October 19, 2017 Next Review Date: October 2018 Policy contains: Medical marijuana. Cannabis. Tetrahydrocannabinol. Hydrocannabinol. Related policies: None. ABOUT THIS POLICY: Select Health of South Carolina has developed clinical policies to assist with making coverage determinations. Select Health of South Carolina s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peerreviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Select Health of South Carolina when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Select Health of South Carolina s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Select Health of South Carolina s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Select Health of South Carolina will update its clinical policies as necessary. Select Health of South Carolina s clinical policies are not guarantees of payment. Coverage policy Select Health of South Carolina considers the use of botanical marijuana to be investigational and, therefore, not medically necessary (National Academies of Sciences, Engineering, and Medicine [NASEM], 2017; U.S. Food and Drug Administration [FDA], 2017 and 2016). For the purpose of this policy, the term marijuana refers to the dried leaves and flowers of marijuana, and any mixture or preparation thereof, and does not include FDA-approved drugs that may contain active ingredients that are present in marijuana (e.g., dronabinol or nabilone). This policy applies to any method of absorption, including but not limited to smoking, vaporizing, nasal or oral sprays, and oral ingestion. Limitations: None. Alternative covered services: 1

FDA-approved drugs represented in evidence-based practice standards. Background Cannabis, also known as marijuana, is the dried leaves and flowering tops of the cannabis plant, most commonly, cannabis sativa. Cannabis produces terpenophenolic compounds called cannabinoids, which activate specific receptors found throughout the body, particularly in the central nervous system and the immune system, causing pharmacologic effects in the body. Tetrahydrocannabinol (THC) is the main cannabinoid found in cannabis and largely responsible for its psychoactive effects (National Cancer Institute [NCI], 2017). Cannabis may be taken by mouth or inhaled. When taken by mouth (in baked products or as an herbal tea), THC is processed by the liver, making an additional psychoactive chemical. When cannabis is smoked and inhaled, cannabinoids quickly enter the bloodstream. The additional psychoactive chemical is produced in smaller amounts than when taken by mouth (NCI, 2017). Medical marijuana refers to the use of cannabis and its constituents as a physician-recommended form of medicine or herbal therapy. Marijuana or marijuana-derived products are being used for a number of medical conditions, including AIDS wasting, epilepsy, neuropathic pain, treatment of spasticity associated with multiple sclerosis (MS), and cancer- and chemotherapy-induced nausea and vomiting (CINV) (FDA, 2017). The risks and benefits of its medicinal use are unclear (NCI, 2017). The most rigorous studies have reported adverse events associated with its recreational use, but extrapolating results of recreational cannabis use cannot be expected to occur with medical marijuana use. The amounts used, the existence of comorbidities, and the methods of drug delivery may differ between the two populations. Therefore, there is a strong scientific rationale for evaluating medical marijuana separately (Wang, 2008). Regulation: In the United States, marijuana is a Schedule I controlled substance requiring special licensing for its use; it has no recognized medical use, carries a high risk of dependency, and is illegal to use and distribute (21 U.S.C. 801). The FDA is responsible for the approval and marketing of drugs for medical use, including controlled substances (FDA, 2017). Several states have either passed laws that remove state restrictions on the medical use of marijuana and its derivatives, or are considering doing so. To date, the FDA has not approved a marketing application for a drug product containing or derived from botanical marijuana, and has not found any such product to be safe and effective for any indication (FDA, 2017). The FDA has approved two drugs that have synthetic THC as an active ingredient. Dronabinol, marketed as Marinol (AbbVie Inc., North Chicago, Illinois) and Syndros (Insys Therapeutics, Inc., Chandler, Arizona), is approved for anorexia associated with weight loss in patients with AIDS and for nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to 2

conventional antiemetic treatments. Nabilone is marketed as Cesamet (Valeant Pharmaceuticals, Aliso Viejo, California), which has a chemical structure similar to THC and is approved for CINV in patients who have failed to respond adequately to conventional antiemetic treatments. Dronabinol and nabilone are administered orally in capsule form (FDA, 2017). In April 2014, the FDA granted Fast-Track designation to the investigational drug product Sativex (GW Pharmaceuticals, United Kingdom) (FDA, 2016). Sativex is composed primarily of cannabidiol (CBD) and THC; it is administered as a metered dose oromucosal spray for the treatment of pain in patients with advanced cancer, who experience inadequate analgesia during optimized chronic opioid therapy. Sativex is currently in Phase III clinical trials for this indication. On June 6, 2014, the FDA granted Fast-Track designation to Epidiolex (GW Pharmaceuticals, United Kingdom), for treatment of Dravet syndrome, a rare and catastrophic treatment-resistant form of childhood epilepsy. Fast-Track designation provides for more frequent meetings and communications with the FDA to discuss the drug s development plan and ensures collection of appropriate data needed to support drug approval, including the design of the proposed clinical trials and use of biomarkers (FDA, 2016). Medical uses of smoked, inhaled, ingested, or sprayed botanical marijuana are the focus of this clinical policy. This policy excludes Marinol, Cesamet, Sativex, or Epidiolex for clinical use, and marijuana for recreational use. Searches Select Health of South Carolina searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on August 30, 2017. Search terms were: "Cannabis"(MeSH) and "Medical Marijuana"(MeSH). We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. 3

Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings We identified 10 systematic reviews for this policy. The systematic reviews examined the safety and effectiveness of cannabis and cannabinoids for several medical uses. These uses include wasting and cachexia in patients with HIV/AIDS, pain and spasticity in patients with amyotrophic lateral sclerosis (ALS)/motor neuron disease, antiemesis for CINV, ataxia associated with MS, dyskinesia in Parkinson s disease, intraocular pressure in glaucoma, and symptoms of asthma. We found no economic analyses or evidence-based guidelines for this policy. The evidence is insufficient to support the use of botanical (smoked) marijuana for medical use. Most of the available evidence from randomized controlled trials (RCTs) with placebo controls was intended to assess the safety and efficacy of oral delta-9-thc in patients who had failed conventional therapies. Relatively few RCTs have evaluated the safety and efficacy of smoked marijuana for medical use. All of the studies involved small numbers of patients and were of short duration, lasting from several days to weeks, depending on the condition being treated. Studies carried out in the 1970s and 1980s compared medical marijuana to outdated standards of care and lacked measurement of benefits and harms associated with long-term inhaled marijuana use. The paucity and poor quality of the evidence make it difficult to compare botanical marijuana with current pharmaceuticals that have received regulatory approval under more rigorous experimental conditions. Marijuana contains a variable mixture of poorly defined biologically active compounds and the level of THC fluctuates significantly between samples, making it impossible to quantify by inspection. The concept of a predictable, quantifiable "dose" is a fundamental principle of medical therapy, but few (if any) of the prescribing criteria of medical pharmacology can be met in the case of smoked or ingested botanical marijuana (Fisher, 2002). Our searches and a report by the Canadian Agency for Drugs and Technologies in Health (CADTH) found no evidence-based guidelines supporting the use of medical marijuana for specific medical conditions (CADTH, 2013). Practitioners recognized that marijuana might have treatment potential for certain medical symptoms. However, they are not uniform in their support for, or opposition to, medical marijuana. Several major medical organizations in the United States have not endorsed the use of medical marijuana, but most have called for expedited clinical research to discern its safety, dosage, and effectiveness, particularly of cannabinoids rather than smoked marijuana (American Academy of Pediatrics, 2015; American Academy of Child and Adolescent Psychiatry, 2012; American College of Physicians, 2008). Policy updates: 4

In 2015, we identified one new systematic review for this update (Koppel, 2014). The results of the review do not change the previous conclusions. Therefore, no changes to the policy are warranted. In 2016, we identified two new evidence-based guidelines, four systematic review and meta-analyses, and one large epidemiologic study for this policy. Guidelines by the American Congress of Obstetricians and Gynecologists (ACOG) and the American Academy of Neurology (AAN) cite the limited evidence supporting the safety and efficacy of medical cannabis use in pregnant women and persons with MS, respectively (ACOG, 2015; Yadav, 2014). Both guidelines highlight concerns for known adverse effects and knowledge gaps in standardized administration of cannabis, long-term effects, and interactions with other drug treatments. Results of three new systematic reviews and meta-analyses suggest botanical cannabis offers short-term relief of chronic neuropathic pain with non-serious side effects when used in conjunction with traditional analgesics, but comparisons to treatment alternatives are lacking, as are long-term safety and effectiveness data (Andreae, 2015; Deshpande, 2015; Whiting, 2015). In addition, Whiting (2015) found low-to-moderate quality evidence that botanical cannabis improved CINV, weight gain in HIV infection, sleep disorders, and Tourette syndrome, but also increased the risk of adverse effects, including some serious ones such as psychosis. Gurney (2015) found low-quality evidence supporting an association between cannabis use and increased risk of developing non-seminoma testicular germ cell cancer, particularly among current users, at least weekly users and chronic users (> 10 years), compared to those who never used cannabis. Finally, a large epidemiologic survey of 34,653 adults aged 18 years in the United States found cannabis use was significantly associated with an increased risk for several substance use disorders (SUDs) (Blanco, 2016). Based on the new evidence, the benefits of botanical cannabis for medical use do not outweigh the risks of adverse events for any indication. According to the FDA, additional research of its safety and effectiveness should be registered by the Drug Enforcement Administration and conducted under an FDA investigational new drug application and research protocol using medical grade cannabis supplied by the National Institute on Drug Abuse (FDA, 2016). In 2017, we added one evidence-based guideline by the American Society of Clinical Oncology (ASCO) that addressed medical marijuana use for treating chronic cancer pain in adults (Paice, 2016), and one comprehensive systematic review of the health effects of cannabis and cannabinoid use for multiple indications (National Academies of Sciences, Engineering, and Medicine [NASEM], 2017). The NASEM review included the systematic reviews identified previously in this policy. While fairly high quality evidence from controlled studies supports the effectiveness of medical cannabis for treating chronic pain of various etiologies, most of the studies were carried out in other countries (NASEM, 2017). Very little is known about the efficacy, dose, routes of administration, or side effects of commonly used and commercially available cannabis products in the United States. Moreover, many of the cannabis products sold in state-regulated markets do not resemble the products available for research at the federal level in the United States. There is insufficient evidence upon which to base 5

conclusions about therapeutic risks and benefits for other medical indications (NASEM, 2017). The new information does not change previous policy findings, and no policy changes are warranted. Summary of clinical evidence: Citation NASEM (2017) Health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research (Results for smoking or inhaled cannabis only) Blanco (2016) Cannabis use and risk of psychiatric disorders Paice (2016) for ASCO Content, Methods, Recommendations Systematic review of selected fair-to-good quality systematic reviews (published since 2011) and subsequent high-quality primary research for multiple medical conditions. Evidence of treatment effectiveness of cannabis: - Sufficient evidence for pain, but very little is known about the efficacy, dose, routes of administration, or side effects of commonly used and commercially available cannabis products in the United States. - Insufficient for CINV. - Limited for increasing appetite and decreasing weight loss associated with HIV/AIDS. - No or insufficient evidence for all other indications. Limited evidence of no association between smoking cannabis and risk for certain cancers (i.e., lung, head and neck) in adults. Limited evidence of an association between cannabis smoking and non-seminomatype testicular germ cell tumors (current, frequent, or chronic cannabis smoking). No or insufficient evidence of association between cannabis use and incidence of esophageal cancer. A nationally representative sample of 34,653 U.S. adults aged 18 years interviewed three years apart in the National Epidemiologic Survey on Alcohol and Related Conditions (wave 1, 2001-2002; wave 2, 2004-2005) using multiple regression analysis and propensity score matching used to estimate association between cannabis use at wave 1 and incidence and prevalence of Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV psychiatric disorders at wave 2. Within the general population, cannabis use in wave 1 was significantly associated with an increased risk for several SUDs in wave 2 (odds ratio [OR], 95% confidence interval [CI]): - Any SUD: 6.2 (4.1-9.4). - Any alcohol use disorder: 2.7 (1.9-3.8). - Any cannabis use disorder: 9.5 (6.4-14.1). - Any other drug use disorder: 2.6 (1.6-4.4). - Nicotine dependence: 1.7 (1.2-2.4). - But not mood disorder (1.1, 0.8-1.4) or anxiety disorder (0.9, 0.7-1.1). Guideline: management of chronic pain in survivors of adult cancer Clinicians may follow specific state regulations that allow access to medical cannabis or cannabinoids for patients with chronic pain after a consideration of the potential benefits and risks of the available formulations. (Evidence-based; benefits outweigh harms; evidence quality: intermediate; strength of recommendation: moderate). 6

Citation ACOG Committee Opinion (2015) Guideline for marijuana use during pregnancy and lactation Andreae (2015) Inhaled cannabis for chronic neuropathic pain Deshpande (2015) Medical marijuana for chronic non-cancer pain (CNCP) Gurney (2015) Content, Methods, Recommendations There are no FDA-approved indications, contraindications, safety precautions, or recommendations regarding its use during pregnancy and lactation. There are no standardized formulations, dosages, or delivery systems. Obstetrician gynecologists should be discouraged from prescribing or suggesting the use of marijuana for medicinal purposes during preconception, pregnancy, and lactation. Pregnant women or women contemplating pregnancy should be encouraged to discontinue use of medical marijuana in favor of alternative therapies with better pregnancy-specific safety data. High-quality studies regarding the effects of marijuana and other cannabis products on pregnancy and lactation are needed. A meta-analysis of individual patient data from five RCTs (178 participants with chronic neuropathic pain with 405 observed responses) following patients for days to weeks. Inhaled cannabis may provide short-term pain relief for one in five to six patients. Results limited by small number of studies and participants, short follow up, shortcomings in allocation concealment, and considerable attrition. Pragmatic trials are needed to evaluate the long-term benefits and risks. Systematic review of six RCTs (226 total patients) of medical marijuana in CNCP with other concomitant analgesics including opioids and anticonvulsants. Overall quality: moderate. All limited by lack of masking, short duration (maximum of 5 days), variability in dosing and strength of delta-9-thc, and lack of functional outcomes. Three of six trials reported clinically meaningful pain reduction using low-dose (< 34 mg/d) medical marijuana in refractory neuropathic pain of moderate severity in conjunction with traditional analgesics with non-serious side effects. Functional assessment and quality of life domains not reported. Comparisons to other treatment alternatives are lacking, and long-term psychoactive and neurocognitive effects remain unknown. Evidence does not support generalizing the use of medical marijuana to all CNCP conditions. Cannabis exposure and risk of testicular cancer Systematic review and meta-analysis of three case-control studies (719 total cases, 1,419 controls) conducted in the United States in the 1990s. Overall quality: low with a high risk of bias. Limited by low and differential response rates between groups, non-validated self-reported use, and lack of blinding. Current use of cannabis (pooled summary OR 1.62, 95% CI 1.13-2.31), using cannabis at least weekly (1.92, 1.35-2.72) and long duration (> 10 years) of cannabis use (1.50, 1.08-2.09) are all associated with increased risk of developing a nonseminoma testicular germ cell tumor compared to those who never used cannabis. 7

Citation Whiting (2015) Cannabinoids for medical use: CINV, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome Koppel (2014) MS, epilepsy, and movement disorders. Yadav (2014) for the AAN Evidence-based guideline: complementary and alternative medicine in MS Lutge (2013) Content, Methods, Recommendations Evidence of a relationship between cannabis use and the development of seminoma tumors was inconclusive. Systematic review and meta-analysis of 79 RCTs (6,462 total participants). Overall quality: low to moderate. Only four judged at low risk of bias. Mostly placebocontrolled. Most trials showed non-statistically significant improvement in symptoms. Moderate-quality evidence supports cannabinoid use for treatment of chronic pain and spasticity. Low-quality evidence suggests cannabinoid use improved CINV, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term adverse events (AE), including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. Systematic review of 34 studies (eight RCTs) (1948 November 2013) including two controlled studies of smoked marijuana. For spasticity, central pain or painful spasms in MS or seizure disorders, smoked marijuana is of unclear efficacy. Cognitive impairment is a significant adverse effect with smoked marijuana use. Comparative effectiveness to other drugs needs to be studied. Guideline included two non-rcts of inhaled cannabis use (57 total patients with mixed types of MS). Conflicting findings with respect to short-term reductions in spasticity, pain, measures of posture and balance and cognitive performance. Cannabinoids may cause adverse effects. Clinicians should exercise caution regarding standardized vs. non-standardized cannabis extracts and overall quality control/non-regulation. Interaction with MS disease-modifying therapies is unknown. Insufficient evidence to recommend for or against cannabis use. Cochrane review HIV/AIDS Seven RCTs (eight publications) of effects of cannabis (in its natural or artificially produced form) either smoked or ingested, on morbidity or mortality of patients infected with HIV. Overall quality: low. Short duration (21 days to 84 days); small numbers; allocation concealment variable but only dronabinol was expected to be more easily blinded; variable outcomes measured for change in weight, body fat, appetite, caloric intake, nausea and vomiting, performance and mood. Insufficient evidence for the efficacy and safety of cannabis and cannabinoids in persons with HIV/AIDS. Long-term data showing a sustained effect on AIDS-related 8

Citation Content, Methods, Recommendations morbidity, mortality and safety in patients on effective antiretroviral therapy, not available. References Professional society guidelines/other: ACOG Committee opinion No. 637: marijuana use during pregnancy and lactation. Obstet Gynecol. 2015; 126(1): 234 238. American Academy of Pediatrics. The Impact of Marijuana Policies on Youth: Clinical, Research, and Legal Update. Pediatrics. 2015; 135(3): 584. DOI: 10.1542/peds.digest1353. Medical marijuana policy statement. American Academy of Child and Adolescent Psychiatry website. http://www.aacap.org/aacap/policy_statements/2012/aacap_medical_marijuana_policy_statement.a spx. Accessed August 30, 2017. Rapid response report: reference list. The use of medical marijuana: guidelines and recommendations. 15 January 2013. Canadian Agency for Drugs and Technologies in Health (CADTH) website. http://www.cadth.ca/media/pdf/htis/jan-2013/ra0611%20medical%20marijuana%20final.pdf. Accessed August 30, 2017. Supporting research into the therapeutic role of marijuana. A position paper of the American College of Physicians. American College of Physicians website. https://www.acponline.org/system/files/documents/advocacy/current_policy_papers/assets/medmarij uana.pdf. Accessed August 30, 2017. Yadav V, Bever C, Jr., Bowen J, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2014; 82(12): 1083 1092. Peer-reviewed references: 21 U.S.C. 801. Controlled Substances Act. Andreae MH, Carter GM, Shaparin N, et al. Inhaled Cannabis for Chronic Neuropathic Pain: A Metaanalysis of Individual Patient Data. J Pain. 2015; 16(12): 1221 1232. Blanco C, Hasin DS, Wall MM, et al. Cannabis use and risk of psychiatric disorders: prospective evidence from a us national longitudinal study. JAMA Psychiatry. 2016; 73(4): 388 395. 9

Brettschneider J, Kurent J, Ludolph A. Drug Therapy for Pain in Amyotrophic Lateral Sclerosis or Motor Neuron Disease. Cochrane Database Syst Rev. 2013(6): CD005226. Cannabis and Cannabinoids (PDQ ). Overview. Updated April 7, 2017. National Cancer Institute website. http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional. Accessed September 7, 2016. Deshpande A, Mailis-Gagnon A, Zoheiry N, Lakha SF. Efficacy and adverse effects of medical marijuana for chronic noncancer pain: Systematic review of randomized controlled trials. Can Fam Physician. 2015; 61(8): e372 e381. FDA. News & Events. FDA and Marijuana: Questions and Answers. Page last updated August 15, 2017. FDA website. http://www.fda.gov/newsevents/publichealthfocus/ucm421168.htm. Accessed August 30, 3017. FDA. News & Events. Researching the Potential Medical Benefits and Risks of Marijuana. July 13, 2016. FDA website. http://www.fda.gov/newsevents/testimony/ucm511057.htm. Accessed August 30, 2017. Fisher B, Johnston D, Leake P for the Medical Services Workers' Compensation Board Alberta. Marijuana for medicinal purposes: An evidence-based assessment. June, 2002. Workers' Compensation Board of British Columbia website: https://www.worksafebc.com/en/resources/health-careproviders/guides/marijuana-for-medicinal-purposes-an-evidence-based-assessment?lang=en. Accessed August 30, 2017. Gurney J, Shaw C, Stanley J, Signal V, Sarfati D. Cannabis exposure and risk of testicular cancer: a systematic review and meta-analysis. BMC Cancer. 2015; 15: 897. Koppel BS, Brust JC, Fife T, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014; 82(17): 1556 1563. Lutge EE, Gray A, Siegfried N. The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS. Cochrane Database Syst Rev. 2013; 4: CD005175. National Academies of Sciences, Engineering, and Medicine. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press; 2017. DOI: 10.17226/24625. Wang T, Collet JP, Shapiro S, Ware MA. Adverse Effects of Medical Cannabinoids: A Systematic Review. CMAJ: Canadian Medical Association Journal. 2008; 178(13): 1669 1678. 10

Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: A systematic review and metaanalysis. Jama. 2015; 313(24): 2456 2473. CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): No LCDs identified as of the writing of this policy. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly. CPT Code Description Comment No codes ICD-10 Code Description Comment No codes HCPCS Level ll Code No codes Description Comment 11