- Email: [email protected]
Cannabis and Health Research: Rapid Progress Requires Innovative Research Designs
-
Contents lists available at sciencedirect.com Journal homepage: www.elsevier.com/locate/jval
Cannabis and Health Research: Rapid Progress Requires Innovative Research Designs Kent E. Hutchison, PhD,1,* L. Cinnamon Bidwell, PhD,2 Jarrod M. Ellingson, PhD,1 Angela D. Bryan, PhD1 1 Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA; 2Institute of Cognitive Science, University of Colorado Boulder, Boulder, CO, USA.
A B S T R A C T The United States has witnessed enormous changes concerning the acceptance of medicinal and recreational cannabis use. Sixty-three percent of the US population has access to medicinal cannabis markets, which offer increasingly diverse and potent cannabis products. Considering the rapidly changing cultural, political, and legal landscape, the scientific literature does not adequately inform public policy, medical decision making, or harm reduction approaches. The goals of this paper are to (1) investigate the state of cannabis research on medical conditions commonly treated with cannabis, (2) review the barriers that have led to large gaps between cannabis use and available empirical data, and (3) suggest a path forward with new research designs to address these gaps. Thus, we aim to advance a more nuanced understanding of the barriers to cannabis research and suggest innovative research designs necessary for rapid development of a meaningful knowledge base. Keywords: cannabis, CBD, external validity, FDA, marijuana, observational research, THC. VALUE HEALTH. 2019; -(-):-–-
Introduction The United States has witnessed enormous changes concerning the public acceptance of cannabis in recent years. Thirty states and the District of Columbia have legalized the use of medical cannabis in some form. Despite increased availability and use, there is a dearth of scientific research to guide consumer decisions about the clinical utility and side effects of medical cannabis. This paper addresses 3 broad questions. First, what is the status of the evidence base to guide consumers on the clinical utility of cannabis, particularly for medical conditions for which individuals use cannabis? To address that question, we documented the number of National Institute of Health (NIH)–funded clinical trials on cannabis for 3 medical conditions (pain, seizure disorders, depression or anxiety) and compared those trends to the numbers of trials for alternative other pharmaceutical agents. Second, what are the legal and contextual factors that underlie our current lack of knowledge on the clinical utility of cannabis? In this section, we describe some of the most substantial barriers to advancing science on the medicinal effects of cannabis. Accordingly, our third question addresses how we might move forward to build the evidence base. Here, we identify research designs that can be rapidly deployed to address current barriers and work within the bounds of the current political and legal climate to better understand the health effects of cannabis.
Has Access to Medical Cannabis Outpaced Cannabis Research? In 1999, the National Academy of Sciences Institute of Medicine (IOM) made a call for NIH-funded clinical trials on the medicinal effects of cannabis.1 To determine the success of this call, we searched ClinicalTrials.gov for registered clinical trials in which the active treatment was a compound derived from the Cannabis sativa plant from 1999 to 2018. Specifically, search criteria included trials that met the following: (1) published since the IOM call for cannabis trials (1999); (2) were conducted in the United States; (3) were funded by the NIH; (4) were classified as an interventional study; (5) were classified using the term “randomized,” (6) completed recruitment; (7) had results available; and (8) contained the intervention terms “cannabis,” “marijuana,” or “cannabidiol,” as well as the drug names “Sativex” (GW-1000-02) or “Epidiolex” (GWP42003). We identified only 2 registered, randomized clinical trials (RCTs): 1 for pain in spinal cord injuries (n = 42) and 1 for reward deficiency in schizophrenia (n = 12). When criteria were broadened to include incomplete trials, 6 additional trials were identified; 2 on cannabis for pain in sickle cell disease and neuropathy (n = 155), 2 on individual differences in the subjective response to cannabis (n = 374), 1 on cannabis interactions with other drugs (n = 49), and 1 on the pharmacokinetics of cannabis (n = 80). Pain studies
* Address correspondence to: Kent Hutchison, PhD, Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309. Email: Kent. [email protected] 1098-3015/$36.00 - see front matter Copyright ª 2019, ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. https://doi.org/10.1016/j.jval.2019.05.005
2
- 2019
VALUE IN HEALTH
Figure 1. A comparison of individuals enrolled in registered clinical trials (clinicaltrials.gov) on pain using opioid- and cannabis-based interventions. This flowchart, comparing the number of individuals enrolled in opioid and cannabis trials for pain-related conditions registered on clinicaltrials.gov, suggests that the 1999 Institute of Medicine call for cannabis clinical trials has only led to a few clinical trials with cannabis. These numbers reflect all trials (and their corresponding n values) that have been conducted after the 1999 call from the National Academy of Sciences for NIH-funded clinical trials on the medicinal effects of cannabis. The search for cannabis included the intervention terms “cannabis,” marijuana,” “cannabidiol,” “Sativex” (GW-1000-02), and “Epidiolex” (GWP42003). Of the 200 randomized pain trials, 0.3% of individuals were enrolled in a trial that evaluated the effects of cannabis, and 10.6% were enrolled in a trial that evaluated the effects of opiates. NIH indicates National Institutes of Health.
Opioid Trials
Search Criteria
Cannabis Trials
Pain-Related Conditions 8,121 Trials n = 5,278,817 1,076 Trials n = 189,104
39 Trials n = 8,799
Conducted in the U.S.
432 Trials n = 70,555
3,213 Trials n = 1,084,373
18 Trials n = 2,433
Funded by NIH
35 Trials n = 7,722
358 Trials n = 115,006
5 Trials n = 247
Interventional Studies
33 Trials n = 7,690
272 Trials n = 74,750
5 Trials n = 247
Randomized
25 Trials n = 7,096
200 Trials n = 66,654
represent the largest of the registered clinical trials on cannabis as a treatment since 1999 (3 studies; n = 197). This is dismally small considering that chronic pain is the most commonly cited condition for the use medicinal of cannabis, with 87% to 94% of medical cannabis users reporting use to relieve a pain condition.2,3 In sum, the IOM call almost 20 years ago led to only a handful of clinical trials with cannabis. To further put these numbers in context, we evaluated the number of cannabis trials compared to studies of alternative pharmacologic agents for the 3 most common conditions treated with cannabis: pain, mood or anxiety, and epilepsy or seizure disorders.4 There were 200 trials on pharmacologic agents treating pain (n = 66 654; see Fig. 1). Thus, approximately 1.5% of all registered pain trials since 1999 evaluated the effects of cannabis. For comparison, 12.5% evaluated the effects of opiates (25 trials enrolling 7096 participants). Notably, no trials assessed cannabis as a treatment for depression and anxiety or epilepsy and seizures compared with 222 antidepressant trials (n = 110,435) and 30 antiepileptic or antiseizure medication trials (n = 4,408).
3 Trials n = 197
In contrast to the small number of scientific studies addressing the medical impact of cannabis, legal access has rapidly increased during this period. There are approximately 2 million registered medical cannabis users in the United States,5-7 with likely a much larger number of non-registered individuals who purchase in recreational or black markets but use to treat medical conditions. More broadly, US state-regulated cannabis markets posted $6.7 billion in revenue in 2016, up 30% from the year before (see Fig. 2).8 Consequently, it seems that millions of Americans are spending billions of dollars to purchase cannabis to address specific medical problems, but without evidence to guide effective dosing, routes of administration, different formulations, potential side effects, or drug interactions. Likewise, state-regulated markets offer new cannabis formulations (eg, high-potency concentrates; see Fig. 3) that have rapidly increased in sales and may have medicinal uses, but the risks of these formulations are unknown. Thus, cannabis access and use in the United States have clearly outpaced research on potential medical benefits or risks.
--
3
Figure 2. Current and projected medical and recreational cannabis industry growth through 2021.8 Projected growth in recreational and medical cannabis sales in legal North American markets through 2021. Sales in Washington and Colorado primarily drove 34% growth from 2015 to 2016. Growth is expected to continue with legal recreational sales beginning in Canada and in US states of California and Massachusetts in 2018.
North American legend Cannabis Spending 2015-2021
Sales (Billions of Dollars)
25 $14.9B 20 $10.7B 15
Market
$7.6B
Recreational
$4.2B
10 5
Medical
$2.5B
$1.0B
$1.8B
$4.0B
$4.9B
$5.7B
2015
2016
2017
$7.0B
$7.0B
$7.3B
$7.7B
2018
2019
2020
2021
0
Year
How Did Access to Cannabis Get So Far Ahead of the Evidence Base? Major policy and institutional barriers to research have, perhaps unintentionally, produced a vast knowledge gap in the context of progressive cannabis decriminalization. Our goal is not to review the highly complex sociopolitical context from which these barriers emerged,9 but rather to outline critical barriers that currently impede scientific progress and make specific suggestions for a way forward. The most notable barrier is the schedule I status of cannabis, which is intended for drugs with high abuse potential, no accepted medical use, and a lack of accepted safety for use under medical supervision (eg, medical trials). Importantly, there are 4 problematic implications of this Schedule I status.1 First, schedule I status means that there is only 1 supplier of cannabis that is legal at the federal level (ie, the National Institute on Drug Abuse [NIDA] supply source). Second, schedule I status, when combined with other federal laws, make it almost impossible for scientists at federally funded institutions to conduct
research, unless they use the federal source of cannabis. Third, and perhaps most importantly, the schedule I status makes it very difficult to get an investigational new drug (IND) exemption from the US Food and Drug Administration (FDA) to study cannabis products that are widely used in state-regulated markets, making the FDA a direct barrier to cannabis research today. Indirectly, by limiting the ability of researchers to conduct phase I and II studies, this has undoubtedly led to fewer phase III and IV trials. Finally, a more practical barrier (underscored above) is that the largest sponsor of US research (NIH) sponsors almost no research on the medical effects of cannabis. Each of these barriers is discussed in more detail below. As a schedule I drug, the only federally legal means of obtaining cannabis is the NIDA drug supply. Conducting studies with NIDA research cannabis requires oversight from the Drug Enforcement Agency, whose mission is not to facilitate research, but to prevent the diversion of controlled substances. These and other difficulties in obtaining and working with NIDA research cannabis have been described in detail.10 It is often overlooked,
Figure 3. State of Colorado official reporting on concentrate, edible, and flower cannabis sales in from 2014 to 2017.38,39 In legal markets such as Colorado, sales indicate a shift to new and more potent products. From 2014 to 2017, concentrate sales (345% increase) outpaced edible and flower sales (101% and 81% increases, respectively).
Annual Sales (Millions of Dollars)
Cannabis Concentrates, Edibles, and Flowers Sales Growth in Colorado $815.7M $769.9M
750
$619.3M
500
Fiscal Year 2014
$451.8M
2015
$352.8M
2016 2017
$254.9M
250
$168.3M $79.3M
$173.9M $135.4M $100.5M
$202.0M
0 Concentrates
Edibles
Product
Flower
4
VALUE IN HEALTH
however, that studies using NIDA research cannabis have limited external validity. Federal varieties show differences in the levels of, and ratios among, several cannabinoids compared with statemarket varieties.11 In addition, most products available in stateregulated markets (ie, edibles, concentrates, oils, wax, shatter, topicals, tinctures) are currently unavailable through federal sources.12 This is clearly a problem given the prevalence of these products, and data suggest they are the fastest-growing segments of the legal market. Thus, nearly all prior studies in the United States reporting on the effects of cannabis have been conducted with products that likely do not generalize to those actually used today, possibly underestimating the impact (for better or worse) of cannabis products that are widely available. The schedule I drug classification also impedes research using state-regulated cannabis products. Specifically, legislation allows the federal government to take punitive action against universities engaged in research with products widely available in their respective states by taking away all federal funding. Consequently, even in states with legal access to cannabis, university-based scientists cannot study the health risks and benefits of products that may have major public health implications for residents of their state using standard research methods. Although removing cannabis from schedule I may encourage research using state-regulated cannabis, RCTs would still require FDA approval for an IND. Normally, the drug approval process begins with a new chemical compound being patented, tested in animal and human studies, labeled through the FDA if promising effects with minimal harms are found in clinical samples (phases I-III), and assessed further for side effects and comparative effectiveness (phase IV). The drug approval process costs approximately $2.5 billion and can take up to 10 years. Cannabis does not fit this rubric for drug development. The legal cannabis market already exceeds $6.7 billion per year with thousands of different companies now producing thousands of cannabis products. Neither companies nor independent scientists have incentive to seek patents or an IND or FDA approval for cannabis, which is readily available in state-regulated markets and can even be produced and extracted by patients themselves. Thus, research on state-regulated cannabis products is unlikely to take place until there are changes in FDA requirements for conducting cannabis research. In summary, unique federal policy barriers have severely limited cannabis research, thus contributing to a situation in which public approval and use of cannabis have outpaced the available data. In concrete terms, there are now over 2 million registered medical users,5-7 for whom cannabis has de facto medical indications, despite the lack of clinical trials. This wide knowledge gap, along with increases in cannabis use, highlight the pressing need for research designs that can be immediately deployed in the current regulatory landscape.
How Can Scientists Rapidly Develop the Knowledge Base? With swiftly changing patterns of cannabis use and little known about the health effects of widely available cannabis products, alternative research designs that can elucidate the impact of today’s cannabis products within the bounds of existing federal law are sorely needed. We suggest that the FDA model for phase IV research best fits the current reality of cannabis use, availability, and already established markets. Phase IV research is critical for drug development, focusing on the impact of already developed drugs on safety, public health, and quality of life. Phase IV trials also include comparative effectiveness and cost-
- 2019
effectiveness studies.13 This framework includes pragmatic clinical trials, which are conducted in real-world clinical settings with all treatment-seeking patients (ie, no exclusion criteria), have similar methodological strengths, and balance external and internal validity.14 To achieve these aims, phase IV-style trials use large sample sizes in observational, noninterventional studies in naturalistic settings, as compared to the smaller sample sizes, narrow inclusion criteria, and highly controlled settings of RCTs (eg, phase III trials).15 Accordingly, such phase IV trials yield stronger conclusions about whether and how a drug works in the real world across a wide variety of patients, as the artificial conditions of RCTs may overestimate the effects of a drug.16 Importantly, phase IV-like designs are also unlikely to require an FDA IND regardless of the schedule I status of cannabis because these studies do not meet the NIH definition of a clinical trial. Thus, the FDA model for phase IV trials provides a balance of maximal internal and external validity critical for building the knowledge base for the health effects of cannabis, and it avoids some policy impediments to research. Below, we outline several such research designs, which aim to provide meaningful, useful, and generalizable data on the impact of cannabis on recreational and medical users. Given that conducting RCTs on state-market cannabis is impossible, it is important to compare RCTs to alternative designs. A recent Cochrane review covering 14 systematic reviews (1583 meta-analyses for 228 medical conditions) compared effect sizes from RCTs with those from observational studies for the same medical conditions.17 The odds ratio contrasting outcomes from RCTs to observational studies was 1.08 (CI: .96 to 1.22), indicating no differences. Further, 11 of the 14 reviews showed no difference across study designs, 1 found a larger effect size for observational studies, and 2 found a larger effect size for RCTs. Thus, there may be a slight bias for RCTs to find a larger effect size, particularly among pharmacologic studies. Nevertheless, the authors note that the pharmaceutical industry sponsored most of these trials,18 and the bias toward finding a larger effect may be due to industry support or to negative trials being unpublished.19 Overall, this large and systematic review concludes that observational studies yield results that are highly consistent with RCTs, with a slight bias toward smaller effects in observational studies. Thus, welldesigned observational trials are legal for studying state-market cannabis and would yield findings consistent with RCTs. Given the pressing need that could be served by observational and comparative effectiveness trials, it is important to consider how to carefully design prospective observational trails with cannabis to maximize internal and external validity. To that end, we lean on 3 critical resources: the Agency for Healthcare Research and Quality guidelines for comparative effectiveness trials,20 the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) practices review,13,21 and the Patient-Centered Outcomes Research Institute methodological consensus.22 Regarding observational comparative effectiveness trials, the prospective observational study is the predominant design. In this design, patients choose their treatment rather than being randomized. This design is more likely to introduce confounds that vary by treatment conditions, which limits internal validity compared to RCTs. Nevertheless, this design can be strengthened given the following conditions. The presence of clinical equipoise, meaning that the patient does not have strong beliefs about the effectiveness of the available interventions that would influence intervention selection,21,23 decreases the likelihood of bias. For example, if there are no systematic differences in beliefs that one cannabis product works better than another (eg, potency of D9tetrahydrocannabinol [THC] and cannabidiol [CBD]), future cannabis studies would likely benefit from clinical equipoise. In
--
addition, any confounds across conditions can be measured and modeled to remove this confounding variance,24 and research designs wherein participants serve as their own control (eg, ABAB) can provide additional control where clinical equipoise is not typical. In this case, patient expectancies regarding the effectiveness of a product can be measured and removed statistically.25 Third, propensity score matching can be used to match participants in distinct conditions on a set of measured variables, producing groups that are statistically equivalent on those variables.26 Observational trials are also often weakened by the inability to measure the degree of exposure to the drug, and this is rarely addressed by the study design.21 It is becoming increasingly clear that the degree of exposure to specific cannabinoids, and the ratios of particular cannabinoids to each other, may alter the acute and longer-term effects of cannabis. Further, different cannabinoids have vastly different, sometimes opposing, effects (eg, THC and CBD),27-30 and some cannabinoids and metabolites have unique extended time courses.31 To clarify exposure to different cannabinoids, detailed blood measurements taken at regular intervals during the observational period can provide precise quantification of cannabinoid exposure. This approach is relatively easy to implement because many labs can now estimate the presence of dozens of cannabinoids and metabolites down to 1 ng/mL (eg, THC, CBD, THC-COOH, CBD-A, CBG, CBN, CBN-COOH, CBC, CBG-V, THC-V, THC-V-COOH, and 11OHTHC).32,33 The use of at-home blood collection kits (https:// www.neoteryx.com/) further increases the flexibility and feasibility of this approach. Affordable and effective blood assays are relatively unique to cannabis, making this a major advantage of comparative effectiveness designs for cannabis use relative to other drugs. Thus, it is critical and feasible to include appropriately timed blood draws in observational trials on cannabis, budget for assays of cannabinoid levels, and quantify the relationship between cannabinoid exposure and outcomes. Consequently, evaluating the degree of exposure and pharmacokinetics of cannabis can greatly clarify the mechanisms that drive its effects. Finally, rigor can be increased by thinking critically about the design of observational cannabis trials. The ISPOR supports the assumption that observational studies approximate RCTs, but it is important to design observational studies with the same level of rigor that one would follow for an RCT. The aims, hypotheses, definition of treatment groups, power analyses, sample size considerations, sample ascertainment, attrition, and analytic plan for observational comparative effectiveness trials should all approximate an RCT design as closely as possible. Observational trial designs should focus on individuals who are about to engage in their first treatment, known as an “inception cohort” or “new user” design, to evaluate the comparative effectiveness of pharmacologic treatments.34 By excluding long-term cannabis users and focusing on individuals who have not started regular use of cannabis to treat their condition, this design diminishes the bias owing to differences in the likelihood of attrition and other problems that arise between treatment-naïve and -experienced populations. The ISPOR review cites a recent analysis of the Women’s Health Initiative, which found that when the analysis was limited to new users, observational and RCT data agreed on the effects of hormone replacement.35 Similarly, study designs can prospectively minimize group differences by matching on key variables, thus avoiding biases normally resolved by random assignment. In summary, several study design characteristics can facilitate the ability of observational studies to avoid bias.
5
High-Priority Areas of Research Given that cannabis research currently lags behind state policies and public acceptance, there are many gaps in the knowledge base of the health effects of cannabis that phase IV-like observational and pragmatic trials can address. Next, we describe important research gaps created by the availability and use of state-market products that are not available from federal sources. We then describe gaps on the health benefits and risks of cannabis more generally.
Medical and Health Effects Over half of US states have approved cannabis to treat many health conditions (eg, cancer, seizures). Recently, the National Academy of Sciences summarized the evidence on the health effects of cannabis and concluded that there is valid data to support the therapeutic use of cannabis in pain reduction, multiple sclerosis-related muscle spasms, and chemotherapy-induced nausea or vomiting.36 The committee cited a substantial body of evidence that certain cannabinoids or formulations were effective in preventing or treating those specific conditions. The body of evidence was less conclusive about positive or negative effects for other areas, including immunity, cardiovascular disease, and mental health, leading to a call for more research. Thus, despite the growing perception that cannabis can treat various illnesses, the scientific literature remains small and mixed for many conditions. We are critically in need of evidence describing the short-term, long-term, and mechanistic effects of cannabis and specific cannabinoids across disease and health states. What doses, exposure periods, and routes of administration are most effective across specific conditions and diseases? Are there dosages or preparations that exacerbate disease states or cause harm? Further, how does cannabis interact with concomitant treatments? What side effects most commonly affect quality of life, and can they be mitigated? Do negative or positive effects differ across developmental stages? Do higher potencies and newer formulations increase the risk for harm, such as respiratory illness, inflammatory conditions, metabolic diseases, or cancers? Have these risks increased under legalization? In addition, building up the empirical literature on the endocannabinoid system, which encompasses the receptors and endogenous compounds that interact with exogenous cannabinoids, will provide important knowledge and improve our understanding of the clinical utility of cannabis.37 These research questions address many health conditions relevant to research programs beyond NIDA, whose mission “is to lead the nation in bringing the power of science to bear on drug abuse and addiction.” Thus, it is neither within NIDA’s financial means nor mission to fund all studies into the health risks and benefits of cannabis. Nevertheless, the National Cancer Institute, the National Institutes on Mental Health, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Center on Complementary and Integrative Health all have a substantial stake in understanding the impact of cannabis on health conditions that fall directly under their purview.
Summary and Conclusion The increasing divide between the real world (owing to state laws and public perception) and how science can meaningfully contribute (owing to federal barriers) has led to a situation in
6
which patients and policymakers lack the evidence needed to make sound decisions regarding cannabis. Further, state markets are rapidly changing, with a wide and growing variety of products marketed to patients and recreational users. Thus, the production of newer forms of cannabis will create even more unanswered public health questions about the health effects of these products. For the cancer patient dealing with devastating side effects of treatment, the chronic pain patient who is desperate for relief without opiates, or the family with a small child suffering from intractable seizures, this situation is unacceptable. From a public health and policy perspective, this situation is irresponsible. Fortunately, there may be a path forward to address research questions on the effects of cannabis on medical, behavioral, and biological processes that involve NIH-funded, well-designed observational trials. Phase IV-style observational, pragmatic, and comparative effectiveness designs for cannabis would elucidate how the drug is used in the real world, document potential benefits, and help monitor for negative consequences and emerging side effects. Our recommendation is that research move forward using post-marketing, observational designs that are noninterventional, do not meet the NIH definition of a clinical trial, are not intended to promote any particular product, nor serve as the basis for an FDA indication for any particular product, but do inform policymakers, clinicians, and patients about the health effects of cannabis. By increasing the number of observational trial designs that answer important public health questions about cannabis, policymakers, patients, and consumers will be able to base decisions on science, rather than anecdotal information.
REFERENCES 1. 2.
3. 4.
5. 6.
7.
8. 9. 10. 11.
12.
13.
- 2019
VALUE IN HEALTH
Benson Jr JA, Watson Jr SJ, Joy JE, et al. Marijuana and Medicine: Assessing the Science Base. National Academies Press; 1999. Light MK, Orens A, Lewandowski B, Pickton T. Market size and demand for marijuana in Colorado. Colorado Department of Revenue. https://www. colorado.gov/pacific/sites/default/files/Market%20Size%20and%20Demand% 20Study,%20July%209,%202014%5B1%5D.pdf. Accessed April 12, 2017. Ilgen MA, Bohnert K, Kleinberg F, et al. Characteristics of adults seeking medical marijuana certification. Drug Alcohol Depend. 2013;132(3):654–659. Reinarman C, Nunberg H, Lanthier F, Heddleston T. Who are medical marijuana patients? Population characteristics from nine California assessment clinics. J Psychoactive Drugs. 2011;43(2):128–135. Fairman BJ. Trends in registered medical marijuana participation across 13 US states and District of Columbia. Drug Alcohol Depend. 2016;159:72–79. ProCon.org. Number of legal medical marijuana patients. http://medicalmar ijuana.procon.org/view.resource.php?resourceID=006445. Accessed April 26, 2017. Department of Health. Medical marijuana program update.https://doh.dc. gov/sites/default/files/dc/sites/doh/publication/attachments/MMPProgramUpdate Memo140918docx.pdf. ArcView Market Research. The state of legal marijuana markets, 5th Edition. Executive Summary.https://www.arcviewmarketresearch.com. Stith SS, Vigil JM. Federal barriers to cannabis research. Science. 2016;352(6290):1182. Nutt DJ, King LA. Nichols DE. Effects of schedule I drug laws on neuroscience research and treatment innovation. Nat Rev Neurosci. 2013;14(8):577–585. National Institute on Drug Abuse. Marijuana plant material available from the NIDA Drug Supply Program.https://www.drugabuse.gov/researchers/ research-resources/nida-drug-supply-program-dsp/marijuana-plant-materialavailable-nida-drug-supply-program. Accessed April 12, 2017. Vergara D, Bidwell LC, Gaudino R, et al. Compromised external validity: federally produced cannabis does not reflect legal markets. Sci Rep. 2017;7:46528. Ramsey S, Willke R, Briggs A, et al. Good research practices for costeffectiveness analysis alongside clinical trials: the ISPOR RCT-CEA Task Force report. Value Health. 2005;8(5):521–533.
14.
15.
16. 17.
18. 19. 20.
21.
22.
23. 24. 25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35. 36.
37. 38.
39.
Godwin M, Ruhland L, Casson I, et al. Pragmatic controlled clinical trials in primary care: the struggle between external and internal validity. BMC Med Res Methodol. 2003;3(1):28. Luce BR, Kramer JM, Goodman SN, et al. Rethinking randomized clinical trials for comparative effectiveness research: the need for transformational change. Ann Intern Med. 2009;151(3):206–209. Suvarna V. Phase IV of drug development. Perspect Clin Res. 2010;1(2):57–60. Anglemyer A, Horvath HT, Bero L. Healthcare Outcomes Assessed with Observational Study Designs Compared with Those Assessed in Randomized Trials. Cochrane Library; 2014. Dorsey ER, de Roulet J, Thompson JP, et al. Funding of US biomedical research, 2003-2008. JAMA. 2010;303(2):137–143. Lundh A, Krogsbøll LT, Gøtzsche PC. Sponsors’ participation in conduct and reporting of industry trials: a descriptive study. Trials. 2012;13(1):146. Agency for Healthcare Research and Quality. Methods guide for effectiveness and comparative effectiveness reviews. AHRQ Publication No. 10(14)-EHC063-EF. www.effectivehealthcare.ahrq.gov. Accessed April 12, 2017. Berger ML, Dreyer N, Anderson F, Towse A, Sedrakyan A, Normand S-L. Prospective observational studies to assess comparative effectiveness: the ISPOR good research practices task force report. Value Health. 2012;15(2):217–230. Selby JV, Beal AC, Frank L. The Patient-Centered Outcomes Research Institute (PCORI) national priorities for research and initial research agenda. JAMA. 2012;307(15):1583–1584. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med. 1987;317(3):141–145. Cohen J, Cohen P, West SG, Aiken LS. Applied Multiple Regression/Correlation Analysis for the Behavioral Sciences. Routledge; 2013. Rutherford BR, Wall MM, Glass A, Stewart JW. The role of patient expectancy in placebo and nocebo effects in antidepressant trials. J Clin Psychiatry. 2014;75(10):1040–1046. Haviland A, Nagin DS, Rosenbaum PR. Combining propensity score matching and group-based trajectory analysis in an observational study. Psychol Methods. 2007;12(3):247–267. Englund A, Morrison PD, Nottage J, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol (Oxf). 2013;27(1):19–27. Vann RE, Gamage TF, Warner JA, et al. Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of D9tetrahydrocannabinol. Drug Alcohol Depend. 2008;94(1):191–198. de Mello Schier AR, de Oliveira Ribeiro NP, Coutinho DS, et al. Antidepressant-like and anxiolytic-like effects of cannabidiol: a chemical compound of cannabis sativa. CNS Neurol Disord Drug Targets. 2014;13(6):953–960. Morgan CJA, Gardener C, Schafer G, et al. Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like symptoms and psychological well-being. Psychol Med. 2012;42(2):391–400. Bergamaschi MM, Karschner EL, Goodwin RS, et al. Impact of prolonged cannabinoid excretion in chronic daily cannabis smokers’ blood on per se drugged driving laws. Clin Chem. 2013;59(3):519–526. Aizpurua-Olaizola O, Zarandona I, Ortiz L, Navarro P, Etxebarria N, Usobiaga A. Simultaneous quantification of major cannabinoids and metabolites in human urine and plasma by HPLC-MS/MS and enzyme-alkaline hydrolysis. Drug Test Anal. 2017;9(4):626–633. Klawitter J, Sempio C, Mörlein S, et al. An atmospheric pressure chemical ionization MS/MS assay using online extraction for the analysis of 11 cannabinoids and metabolites in human plasma and urine. Ther Drug Monit. 2017;39(5):556–564. Ray LA, Hutchison KE. A polymorphism of the m-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans. Alcohol Clin Exp Res. 2004;28(12):1789–1795. Hannan EL. Randomized clinical trials and observational studies. JACC Cardiovasc Interv. 2008;1(3):211–217. National Academies of Sciences. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. National Academies Press; 2017. Hillard CJ. Circulating endocannabinoids: from whence do they come and where are they going? Neuropsychopharmacology. 2018;43(1):155–172. Orens A, Light MK, Lewandowski B, Rowberry J, Saloga C. Market size and demand for marijuana in Colorado: 2017 market update. Colorado Department of Revenue. https://www.colorado.gov/pacific/marijuana/news/ market-size-and-demand-study-marijuana-colorado. Accessed April 9, 2019. Colorado Department of Revenue. Marijuana sales reports.https://www. colorado.gov/pacific/revenue/colorado-marijuana-sales-reports. Accessed April 9, 2019.
Contents lists available at sciencedirect.com Journal homepage: www.elsevier.com/locate/jval
Cannabis and Health Research: Rapid Progress Requires Innovative Research Designs Kent E. Hutchison, PhD,1,* L. Cinnamon Bidwell, PhD,2 Jarrod M. Ellingson, PhD,1 Angela D. Bryan, PhD1 1 Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA; 2Institute of Cognitive Science, University of Colorado Boulder, Boulder, CO, USA.
A B S T R A C T The United States has witnessed enormous changes concerning the acceptance of medicinal and recreational cannabis use. Sixty-three percent of the US population has access to medicinal cannabis markets, which offer increasingly diverse and potent cannabis products. Considering the rapidly changing cultural, political, and legal landscape, the scientific literature does not adequately inform public policy, medical decision making, or harm reduction approaches. The goals of this paper are to (1) investigate the state of cannabis research on medical conditions commonly treated with cannabis, (2) review the barriers that have led to large gaps between cannabis use and available empirical data, and (3) suggest a path forward with new research designs to address these gaps. Thus, we aim to advance a more nuanced understanding of the barriers to cannabis research and suggest innovative research designs necessary for rapid development of a meaningful knowledge base. Keywords: cannabis, CBD, external validity, FDA, marijuana, observational research, THC. VALUE HEALTH. 2019; -(-):-–-
Introduction The United States has witnessed enormous changes concerning the public acceptance of cannabis in recent years. Thirty states and the District of Columbia have legalized the use of medical cannabis in some form. Despite increased availability and use, there is a dearth of scientific research to guide consumer decisions about the clinical utility and side effects of medical cannabis. This paper addresses 3 broad questions. First, what is the status of the evidence base to guide consumers on the clinical utility of cannabis, particularly for medical conditions for which individuals use cannabis? To address that question, we documented the number of National Institute of Health (NIH)–funded clinical trials on cannabis for 3 medical conditions (pain, seizure disorders, depression or anxiety) and compared those trends to the numbers of trials for alternative other pharmaceutical agents. Second, what are the legal and contextual factors that underlie our current lack of knowledge on the clinical utility of cannabis? In this section, we describe some of the most substantial barriers to advancing science on the medicinal effects of cannabis. Accordingly, our third question addresses how we might move forward to build the evidence base. Here, we identify research designs that can be rapidly deployed to address current barriers and work within the bounds of the current political and legal climate to better understand the health effects of cannabis.
Has Access to Medical Cannabis Outpaced Cannabis Research? In 1999, the National Academy of Sciences Institute of Medicine (IOM) made a call for NIH-funded clinical trials on the medicinal effects of cannabis.1 To determine the success of this call, we searched ClinicalTrials.gov for registered clinical trials in which the active treatment was a compound derived from the Cannabis sativa plant from 1999 to 2018. Specifically, search criteria included trials that met the following: (1) published since the IOM call for cannabis trials (1999); (2) were conducted in the United States; (3) were funded by the NIH; (4) were classified as an interventional study; (5) were classified using the term “randomized,” (6) completed recruitment; (7) had results available; and (8) contained the intervention terms “cannabis,” “marijuana,” or “cannabidiol,” as well as the drug names “Sativex” (GW-1000-02) or “Epidiolex” (GWP42003). We identified only 2 registered, randomized clinical trials (RCTs): 1 for pain in spinal cord injuries (n = 42) and 1 for reward deficiency in schizophrenia (n = 12). When criteria were broadened to include incomplete trials, 6 additional trials were identified; 2 on cannabis for pain in sickle cell disease and neuropathy (n = 155), 2 on individual differences in the subjective response to cannabis (n = 374), 1 on cannabis interactions with other drugs (n = 49), and 1 on the pharmacokinetics of cannabis (n = 80). Pain studies
* Address correspondence to: Kent Hutchison, PhD, Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309. Email: Kent. [email protected] 1098-3015/$36.00 - see front matter Copyright ª 2019, ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. https://doi.org/10.1016/j.jval.2019.05.005
2
- 2019
VALUE IN HEALTH
Figure 1. A comparison of individuals enrolled in registered clinical trials (clinicaltrials.gov) on pain using opioid- and cannabis-based interventions. This flowchart, comparing the number of individuals enrolled in opioid and cannabis trials for pain-related conditions registered on clinicaltrials.gov, suggests that the 1999 Institute of Medicine call for cannabis clinical trials has only led to a few clinical trials with cannabis. These numbers reflect all trials (and their corresponding n values) that have been conducted after the 1999 call from the National Academy of Sciences for NIH-funded clinical trials on the medicinal effects of cannabis. The search for cannabis included the intervention terms “cannabis,” marijuana,” “cannabidiol,” “Sativex” (GW-1000-02), and “Epidiolex” (GWP42003). Of the 200 randomized pain trials, 0.3% of individuals were enrolled in a trial that evaluated the effects of cannabis, and 10.6% were enrolled in a trial that evaluated the effects of opiates. NIH indicates National Institutes of Health.
Opioid Trials
Search Criteria
Cannabis Trials
Pain-Related Conditions 8,121 Trials n = 5,278,817 1,076 Trials n = 189,104
39 Trials n = 8,799
Conducted in the U.S.
432 Trials n = 70,555
3,213 Trials n = 1,084,373
18 Trials n = 2,433
Funded by NIH
35 Trials n = 7,722
358 Trials n = 115,006
5 Trials n = 247
Interventional Studies
33 Trials n = 7,690
272 Trials n = 74,750
5 Trials n = 247
Randomized
25 Trials n = 7,096
200 Trials n = 66,654
represent the largest of the registered clinical trials on cannabis as a treatment since 1999 (3 studies; n = 197). This is dismally small considering that chronic pain is the most commonly cited condition for the use medicinal of cannabis, with 87% to 94% of medical cannabis users reporting use to relieve a pain condition.2,3 In sum, the IOM call almost 20 years ago led to only a handful of clinical trials with cannabis. To further put these numbers in context, we evaluated the number of cannabis trials compared to studies of alternative pharmacologic agents for the 3 most common conditions treated with cannabis: pain, mood or anxiety, and epilepsy or seizure disorders.4 There were 200 trials on pharmacologic agents treating pain (n = 66 654; see Fig. 1). Thus, approximately 1.5% of all registered pain trials since 1999 evaluated the effects of cannabis. For comparison, 12.5% evaluated the effects of opiates (25 trials enrolling 7096 participants). Notably, no trials assessed cannabis as a treatment for depression and anxiety or epilepsy and seizures compared with 222 antidepressant trials (n = 110,435) and 30 antiepileptic or antiseizure medication trials (n = 4,408).
3 Trials n = 197
In contrast to the small number of scientific studies addressing the medical impact of cannabis, legal access has rapidly increased during this period. There are approximately 2 million registered medical cannabis users in the United States,5-7 with likely a much larger number of non-registered individuals who purchase in recreational or black markets but use to treat medical conditions. More broadly, US state-regulated cannabis markets posted $6.7 billion in revenue in 2016, up 30% from the year before (see Fig. 2).8 Consequently, it seems that millions of Americans are spending billions of dollars to purchase cannabis to address specific medical problems, but without evidence to guide effective dosing, routes of administration, different formulations, potential side effects, or drug interactions. Likewise, state-regulated markets offer new cannabis formulations (eg, high-potency concentrates; see Fig. 3) that have rapidly increased in sales and may have medicinal uses, but the risks of these formulations are unknown. Thus, cannabis access and use in the United States have clearly outpaced research on potential medical benefits or risks.
--
3
Figure 2. Current and projected medical and recreational cannabis industry growth through 2021.8 Projected growth in recreational and medical cannabis sales in legal North American markets through 2021. Sales in Washington and Colorado primarily drove 34% growth from 2015 to 2016. Growth is expected to continue with legal recreational sales beginning in Canada and in US states of California and Massachusetts in 2018.
North American legend Cannabis Spending 2015-2021
Sales (Billions of Dollars)
25 $14.9B 20 $10.7B 15
Market
$7.6B
Recreational
$4.2B
10 5
Medical
$2.5B
$1.0B
$1.8B
$4.0B
$4.9B
$5.7B
2015
2016
2017
$7.0B
$7.0B
$7.3B
$7.7B
2018
2019
2020
2021
0
Year
How Did Access to Cannabis Get So Far Ahead of the Evidence Base? Major policy and institutional barriers to research have, perhaps unintentionally, produced a vast knowledge gap in the context of progressive cannabis decriminalization. Our goal is not to review the highly complex sociopolitical context from which these barriers emerged,9 but rather to outline critical barriers that currently impede scientific progress and make specific suggestions for a way forward. The most notable barrier is the schedule I status of cannabis, which is intended for drugs with high abuse potential, no accepted medical use, and a lack of accepted safety for use under medical supervision (eg, medical trials). Importantly, there are 4 problematic implications of this Schedule I status.1 First, schedule I status means that there is only 1 supplier of cannabis that is legal at the federal level (ie, the National Institute on Drug Abuse [NIDA] supply source). Second, schedule I status, when combined with other federal laws, make it almost impossible for scientists at federally funded institutions to conduct
research, unless they use the federal source of cannabis. Third, and perhaps most importantly, the schedule I status makes it very difficult to get an investigational new drug (IND) exemption from the US Food and Drug Administration (FDA) to study cannabis products that are widely used in state-regulated markets, making the FDA a direct barrier to cannabis research today. Indirectly, by limiting the ability of researchers to conduct phase I and II studies, this has undoubtedly led to fewer phase III and IV trials. Finally, a more practical barrier (underscored above) is that the largest sponsor of US research (NIH) sponsors almost no research on the medical effects of cannabis. Each of these barriers is discussed in more detail below. As a schedule I drug, the only federally legal means of obtaining cannabis is the NIDA drug supply. Conducting studies with NIDA research cannabis requires oversight from the Drug Enforcement Agency, whose mission is not to facilitate research, but to prevent the diversion of controlled substances. These and other difficulties in obtaining and working with NIDA research cannabis have been described in detail.10 It is often overlooked,
Figure 3. State of Colorado official reporting on concentrate, edible, and flower cannabis sales in from 2014 to 2017.38,39 In legal markets such as Colorado, sales indicate a shift to new and more potent products. From 2014 to 2017, concentrate sales (345% increase) outpaced edible and flower sales (101% and 81% increases, respectively).
Annual Sales (Millions of Dollars)
Cannabis Concentrates, Edibles, and Flowers Sales Growth in Colorado $815.7M $769.9M
750
$619.3M
500
Fiscal Year 2014
$451.8M
2015
$352.8M
2016 2017
$254.9M
250
$168.3M $79.3M
$173.9M $135.4M $100.5M
$202.0M
0 Concentrates
Edibles
Product
Flower
4
VALUE IN HEALTH
however, that studies using NIDA research cannabis have limited external validity. Federal varieties show differences in the levels of, and ratios among, several cannabinoids compared with statemarket varieties.11 In addition, most products available in stateregulated markets (ie, edibles, concentrates, oils, wax, shatter, topicals, tinctures) are currently unavailable through federal sources.12 This is clearly a problem given the prevalence of these products, and data suggest they are the fastest-growing segments of the legal market. Thus, nearly all prior studies in the United States reporting on the effects of cannabis have been conducted with products that likely do not generalize to those actually used today, possibly underestimating the impact (for better or worse) of cannabis products that are widely available. The schedule I drug classification also impedes research using state-regulated cannabis products. Specifically, legislation allows the federal government to take punitive action against universities engaged in research with products widely available in their respective states by taking away all federal funding. Consequently, even in states with legal access to cannabis, university-based scientists cannot study the health risks and benefits of products that may have major public health implications for residents of their state using standard research methods. Although removing cannabis from schedule I may encourage research using state-regulated cannabis, RCTs would still require FDA approval for an IND. Normally, the drug approval process begins with a new chemical compound being patented, tested in animal and human studies, labeled through the FDA if promising effects with minimal harms are found in clinical samples (phases I-III), and assessed further for side effects and comparative effectiveness (phase IV). The drug approval process costs approximately $2.5 billion and can take up to 10 years. Cannabis does not fit this rubric for drug development. The legal cannabis market already exceeds $6.7 billion per year with thousands of different companies now producing thousands of cannabis products. Neither companies nor independent scientists have incentive to seek patents or an IND or FDA approval for cannabis, which is readily available in state-regulated markets and can even be produced and extracted by patients themselves. Thus, research on state-regulated cannabis products is unlikely to take place until there are changes in FDA requirements for conducting cannabis research. In summary, unique federal policy barriers have severely limited cannabis research, thus contributing to a situation in which public approval and use of cannabis have outpaced the available data. In concrete terms, there are now over 2 million registered medical users,5-7 for whom cannabis has de facto medical indications, despite the lack of clinical trials. This wide knowledge gap, along with increases in cannabis use, highlight the pressing need for research designs that can be immediately deployed in the current regulatory landscape.
How Can Scientists Rapidly Develop the Knowledge Base? With swiftly changing patterns of cannabis use and little known about the health effects of widely available cannabis products, alternative research designs that can elucidate the impact of today’s cannabis products within the bounds of existing federal law are sorely needed. We suggest that the FDA model for phase IV research best fits the current reality of cannabis use, availability, and already established markets. Phase IV research is critical for drug development, focusing on the impact of already developed drugs on safety, public health, and quality of life. Phase IV trials also include comparative effectiveness and cost-
- 2019
effectiveness studies.13 This framework includes pragmatic clinical trials, which are conducted in real-world clinical settings with all treatment-seeking patients (ie, no exclusion criteria), have similar methodological strengths, and balance external and internal validity.14 To achieve these aims, phase IV-style trials use large sample sizes in observational, noninterventional studies in naturalistic settings, as compared to the smaller sample sizes, narrow inclusion criteria, and highly controlled settings of RCTs (eg, phase III trials).15 Accordingly, such phase IV trials yield stronger conclusions about whether and how a drug works in the real world across a wide variety of patients, as the artificial conditions of RCTs may overestimate the effects of a drug.16 Importantly, phase IV-like designs are also unlikely to require an FDA IND regardless of the schedule I status of cannabis because these studies do not meet the NIH definition of a clinical trial. Thus, the FDA model for phase IV trials provides a balance of maximal internal and external validity critical for building the knowledge base for the health effects of cannabis, and it avoids some policy impediments to research. Below, we outline several such research designs, which aim to provide meaningful, useful, and generalizable data on the impact of cannabis on recreational and medical users. Given that conducting RCTs on state-market cannabis is impossible, it is important to compare RCTs to alternative designs. A recent Cochrane review covering 14 systematic reviews (1583 meta-analyses for 228 medical conditions) compared effect sizes from RCTs with those from observational studies for the same medical conditions.17 The odds ratio contrasting outcomes from RCTs to observational studies was 1.08 (CI: .96 to 1.22), indicating no differences. Further, 11 of the 14 reviews showed no difference across study designs, 1 found a larger effect size for observational studies, and 2 found a larger effect size for RCTs. Thus, there may be a slight bias for RCTs to find a larger effect size, particularly among pharmacologic studies. Nevertheless, the authors note that the pharmaceutical industry sponsored most of these trials,18 and the bias toward finding a larger effect may be due to industry support or to negative trials being unpublished.19 Overall, this large and systematic review concludes that observational studies yield results that are highly consistent with RCTs, with a slight bias toward smaller effects in observational studies. Thus, welldesigned observational trials are legal for studying state-market cannabis and would yield findings consistent with RCTs. Given the pressing need that could be served by observational and comparative effectiveness trials, it is important to consider how to carefully design prospective observational trails with cannabis to maximize internal and external validity. To that end, we lean on 3 critical resources: the Agency for Healthcare Research and Quality guidelines for comparative effectiveness trials,20 the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) practices review,13,21 and the Patient-Centered Outcomes Research Institute methodological consensus.22 Regarding observational comparative effectiveness trials, the prospective observational study is the predominant design. In this design, patients choose their treatment rather than being randomized. This design is more likely to introduce confounds that vary by treatment conditions, which limits internal validity compared to RCTs. Nevertheless, this design can be strengthened given the following conditions. The presence of clinical equipoise, meaning that the patient does not have strong beliefs about the effectiveness of the available interventions that would influence intervention selection,21,23 decreases the likelihood of bias. For example, if there are no systematic differences in beliefs that one cannabis product works better than another (eg, potency of D9tetrahydrocannabinol [THC] and cannabidiol [CBD]), future cannabis studies would likely benefit from clinical equipoise. In
--
addition, any confounds across conditions can be measured and modeled to remove this confounding variance,24 and research designs wherein participants serve as their own control (eg, ABAB) can provide additional control where clinical equipoise is not typical. In this case, patient expectancies regarding the effectiveness of a product can be measured and removed statistically.25 Third, propensity score matching can be used to match participants in distinct conditions on a set of measured variables, producing groups that are statistically equivalent on those variables.26 Observational trials are also often weakened by the inability to measure the degree of exposure to the drug, and this is rarely addressed by the study design.21 It is becoming increasingly clear that the degree of exposure to specific cannabinoids, and the ratios of particular cannabinoids to each other, may alter the acute and longer-term effects of cannabis. Further, different cannabinoids have vastly different, sometimes opposing, effects (eg, THC and CBD),27-30 and some cannabinoids and metabolites have unique extended time courses.31 To clarify exposure to different cannabinoids, detailed blood measurements taken at regular intervals during the observational period can provide precise quantification of cannabinoid exposure. This approach is relatively easy to implement because many labs can now estimate the presence of dozens of cannabinoids and metabolites down to 1 ng/mL (eg, THC, CBD, THC-COOH, CBD-A, CBG, CBN, CBN-COOH, CBC, CBG-V, THC-V, THC-V-COOH, and 11OHTHC).32,33 The use of at-home blood collection kits (https:// www.neoteryx.com/) further increases the flexibility and feasibility of this approach. Affordable and effective blood assays are relatively unique to cannabis, making this a major advantage of comparative effectiveness designs for cannabis use relative to other drugs. Thus, it is critical and feasible to include appropriately timed blood draws in observational trials on cannabis, budget for assays of cannabinoid levels, and quantify the relationship between cannabinoid exposure and outcomes. Consequently, evaluating the degree of exposure and pharmacokinetics of cannabis can greatly clarify the mechanisms that drive its effects. Finally, rigor can be increased by thinking critically about the design of observational cannabis trials. The ISPOR supports the assumption that observational studies approximate RCTs, but it is important to design observational studies with the same level of rigor that one would follow for an RCT. The aims, hypotheses, definition of treatment groups, power analyses, sample size considerations, sample ascertainment, attrition, and analytic plan for observational comparative effectiveness trials should all approximate an RCT design as closely as possible. Observational trial designs should focus on individuals who are about to engage in their first treatment, known as an “inception cohort” or “new user” design, to evaluate the comparative effectiveness of pharmacologic treatments.34 By excluding long-term cannabis users and focusing on individuals who have not started regular use of cannabis to treat their condition, this design diminishes the bias owing to differences in the likelihood of attrition and other problems that arise between treatment-naïve and -experienced populations. The ISPOR review cites a recent analysis of the Women’s Health Initiative, which found that when the analysis was limited to new users, observational and RCT data agreed on the effects of hormone replacement.35 Similarly, study designs can prospectively minimize group differences by matching on key variables, thus avoiding biases normally resolved by random assignment. In summary, several study design characteristics can facilitate the ability of observational studies to avoid bias.
5
High-Priority Areas of Research Given that cannabis research currently lags behind state policies and public acceptance, there are many gaps in the knowledge base of the health effects of cannabis that phase IV-like observational and pragmatic trials can address. Next, we describe important research gaps created by the availability and use of state-market products that are not available from federal sources. We then describe gaps on the health benefits and risks of cannabis more generally.
Medical and Health Effects Over half of US states have approved cannabis to treat many health conditions (eg, cancer, seizures). Recently, the National Academy of Sciences summarized the evidence on the health effects of cannabis and concluded that there is valid data to support the therapeutic use of cannabis in pain reduction, multiple sclerosis-related muscle spasms, and chemotherapy-induced nausea or vomiting.36 The committee cited a substantial body of evidence that certain cannabinoids or formulations were effective in preventing or treating those specific conditions. The body of evidence was less conclusive about positive or negative effects for other areas, including immunity, cardiovascular disease, and mental health, leading to a call for more research. Thus, despite the growing perception that cannabis can treat various illnesses, the scientific literature remains small and mixed for many conditions. We are critically in need of evidence describing the short-term, long-term, and mechanistic effects of cannabis and specific cannabinoids across disease and health states. What doses, exposure periods, and routes of administration are most effective across specific conditions and diseases? Are there dosages or preparations that exacerbate disease states or cause harm? Further, how does cannabis interact with concomitant treatments? What side effects most commonly affect quality of life, and can they be mitigated? Do negative or positive effects differ across developmental stages? Do higher potencies and newer formulations increase the risk for harm, such as respiratory illness, inflammatory conditions, metabolic diseases, or cancers? Have these risks increased under legalization? In addition, building up the empirical literature on the endocannabinoid system, which encompasses the receptors and endogenous compounds that interact with exogenous cannabinoids, will provide important knowledge and improve our understanding of the clinical utility of cannabis.37 These research questions address many health conditions relevant to research programs beyond NIDA, whose mission “is to lead the nation in bringing the power of science to bear on drug abuse and addiction.” Thus, it is neither within NIDA’s financial means nor mission to fund all studies into the health risks and benefits of cannabis. Nevertheless, the National Cancer Institute, the National Institutes on Mental Health, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Center on Complementary and Integrative Health all have a substantial stake in understanding the impact of cannabis on health conditions that fall directly under their purview.
Summary and Conclusion The increasing divide between the real world (owing to state laws and public perception) and how science can meaningfully contribute (owing to federal barriers) has led to a situation in
6
which patients and policymakers lack the evidence needed to make sound decisions regarding cannabis. Further, state markets are rapidly changing, with a wide and growing variety of products marketed to patients and recreational users. Thus, the production of newer forms of cannabis will create even more unanswered public health questions about the health effects of these products. For the cancer patient dealing with devastating side effects of treatment, the chronic pain patient who is desperate for relief without opiates, or the family with a small child suffering from intractable seizures, this situation is unacceptable. From a public health and policy perspective, this situation is irresponsible. Fortunately, there may be a path forward to address research questions on the effects of cannabis on medical, behavioral, and biological processes that involve NIH-funded, well-designed observational trials. Phase IV-style observational, pragmatic, and comparative effectiveness designs for cannabis would elucidate how the drug is used in the real world, document potential benefits, and help monitor for negative consequences and emerging side effects. Our recommendation is that research move forward using post-marketing, observational designs that are noninterventional, do not meet the NIH definition of a clinical trial, are not intended to promote any particular product, nor serve as the basis for an FDA indication for any particular product, but do inform policymakers, clinicians, and patients about the health effects of cannabis. By increasing the number of observational trial designs that answer important public health questions about cannabis, policymakers, patients, and consumers will be able to base decisions on science, rather than anecdotal information.
REFERENCES 1. 2.
3. 4.
5. 6.
7.
8. 9. 10. 11.
12.
13.
- 2019
VALUE IN HEALTH
Benson Jr JA, Watson Jr SJ, Joy JE, et al. Marijuana and Medicine: Assessing the Science Base. National Academies Press; 1999. Light MK, Orens A, Lewandowski B, Pickton T. Market size and demand for marijuana in Colorado. Colorado Department of Revenue. https://www. colorado.gov/pacific/sites/default/files/Market%20Size%20and%20Demand% 20Study,%20July%209,%202014%5B1%5D.pdf. Accessed April 12, 2017. Ilgen MA, Bohnert K, Kleinberg F, et al. Characteristics of adults seeking medical marijuana certification. Drug Alcohol Depend. 2013;132(3):654–659. Reinarman C, Nunberg H, Lanthier F, Heddleston T. Who are medical marijuana patients? Population characteristics from nine California assessment clinics. J Psychoactive Drugs. 2011;43(2):128–135. Fairman BJ. Trends in registered medical marijuana participation across 13 US states and District of Columbia. Drug Alcohol Depend. 2016;159:72–79. ProCon.org. Number of legal medical marijuana patients. http://medicalmar ijuana.procon.org/view.resource.php?resourceID=006445. Accessed April 26, 2017. Department of Health. Medical marijuana program update.https://doh.dc. gov/sites/default/files/dc/sites/doh/publication/attachments/MMPProgramUpdate Memo140918docx.pdf. ArcView Market Research. The state of legal marijuana markets, 5th Edition. Executive Summary.https://www.arcviewmarketresearch.com. Stith SS, Vigil JM. Federal barriers to cannabis research. Science. 2016;352(6290):1182. Nutt DJ, King LA. Nichols DE. Effects of schedule I drug laws on neuroscience research and treatment innovation. Nat Rev Neurosci. 2013;14(8):577–585. National Institute on Drug Abuse. Marijuana plant material available from the NIDA Drug Supply Program.https://www.drugabuse.gov/researchers/ research-resources/nida-drug-supply-program-dsp/marijuana-plant-materialavailable-nida-drug-supply-program. Accessed April 12, 2017. Vergara D, Bidwell LC, Gaudino R, et al. Compromised external validity: federally produced cannabis does not reflect legal markets. Sci Rep. 2017;7:46528. Ramsey S, Willke R, Briggs A, et al. Good research practices for costeffectiveness analysis alongside clinical trials: the ISPOR RCT-CEA Task Force report. Value Health. 2005;8(5):521–533.
14.
15.
16. 17.
18. 19. 20.
21.
22.
23. 24. 25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35. 36.
37. 38.
39.
Godwin M, Ruhland L, Casson I, et al. Pragmatic controlled clinical trials in primary care: the struggle between external and internal validity. BMC Med Res Methodol. 2003;3(1):28. Luce BR, Kramer JM, Goodman SN, et al. Rethinking randomized clinical trials for comparative effectiveness research: the need for transformational change. Ann Intern Med. 2009;151(3):206–209. Suvarna V. Phase IV of drug development. Perspect Clin Res. 2010;1(2):57–60. Anglemyer A, Horvath HT, Bero L. Healthcare Outcomes Assessed with Observational Study Designs Compared with Those Assessed in Randomized Trials. Cochrane Library; 2014. Dorsey ER, de Roulet J, Thompson JP, et al. Funding of US biomedical research, 2003-2008. JAMA. 2010;303(2):137–143. Lundh A, Krogsbøll LT, Gøtzsche PC. Sponsors’ participation in conduct and reporting of industry trials: a descriptive study. Trials. 2012;13(1):146. Agency for Healthcare Research and Quality. Methods guide for effectiveness and comparative effectiveness reviews. AHRQ Publication No. 10(14)-EHC063-EF. www.effectivehealthcare.ahrq.gov. Accessed April 12, 2017. Berger ML, Dreyer N, Anderson F, Towse A, Sedrakyan A, Normand S-L. Prospective observational studies to assess comparative effectiveness: the ISPOR good research practices task force report. Value Health. 2012;15(2):217–230. Selby JV, Beal AC, Frank L. The Patient-Centered Outcomes Research Institute (PCORI) national priorities for research and initial research agenda. JAMA. 2012;307(15):1583–1584. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med. 1987;317(3):141–145. Cohen J, Cohen P, West SG, Aiken LS. Applied Multiple Regression/Correlation Analysis for the Behavioral Sciences. Routledge; 2013. Rutherford BR, Wall MM, Glass A, Stewart JW. The role of patient expectancy in placebo and nocebo effects in antidepressant trials. J Clin Psychiatry. 2014;75(10):1040–1046. Haviland A, Nagin DS, Rosenbaum PR. Combining propensity score matching and group-based trajectory analysis in an observational study. Psychol Methods. 2007;12(3):247–267. Englund A, Morrison PD, Nottage J, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol (Oxf). 2013;27(1):19–27. Vann RE, Gamage TF, Warner JA, et al. Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of D9tetrahydrocannabinol. Drug Alcohol Depend. 2008;94(1):191–198. de Mello Schier AR, de Oliveira Ribeiro NP, Coutinho DS, et al. Antidepressant-like and anxiolytic-like effects of cannabidiol: a chemical compound of cannabis sativa. CNS Neurol Disord Drug Targets. 2014;13(6):953–960. Morgan CJA, Gardener C, Schafer G, et al. Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like symptoms and psychological well-being. Psychol Med. 2012;42(2):391–400. Bergamaschi MM, Karschner EL, Goodwin RS, et al. Impact of prolonged cannabinoid excretion in chronic daily cannabis smokers’ blood on per se drugged driving laws. Clin Chem. 2013;59(3):519–526. Aizpurua-Olaizola O, Zarandona I, Ortiz L, Navarro P, Etxebarria N, Usobiaga A. Simultaneous quantification of major cannabinoids and metabolites in human urine and plasma by HPLC-MS/MS and enzyme-alkaline hydrolysis. Drug Test Anal. 2017;9(4):626–633. Klawitter J, Sempio C, Mörlein S, et al. An atmospheric pressure chemical ionization MS/MS assay using online extraction for the analysis of 11 cannabinoids and metabolites in human plasma and urine. Ther Drug Monit. 2017;39(5):556–564. Ray LA, Hutchison KE. A polymorphism of the m-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans. Alcohol Clin Exp Res. 2004;28(12):1789–1795. Hannan EL. Randomized clinical trials and observational studies. JACC Cardiovasc Interv. 2008;1(3):211–217. National Academies of Sciences. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. National Academies Press; 2017. Hillard CJ. Circulating endocannabinoids: from whence do they come and where are they going? Neuropsychopharmacology. 2018;43(1):155–172. Orens A, Light MK, Lewandowski B, Rowberry J, Saloga C. Market size and demand for marijuana in Colorado: 2017 market update. Colorado Department of Revenue. https://www.colorado.gov/pacific/marijuana/news/ market-size-and-demand-study-marijuana-colorado. Accessed April 9, 2019. Colorado Department of Revenue. Marijuana sales reports.https://www. colorado.gov/pacific/revenue/colorado-marijuana-sales-reports. Accessed April 9, 2019.