UTopiAH’s life expectancy and death rate are below the Marijuana states, which as of 2017, filled the top quintile state rankings. See Part 16. These parts contain the 2015 Drug Enforcement Agency’s response to a 2011 petition from the Governors of Washington and Rhode Island to legalize Marijuana, a DEA Schedule One Drug. . The letter is viewable at https://www.deadiversion.usdoj.gov/schedules/marijuana/Incoming_Letter_Department%20_HHS.pdf#search=marijuana.

[Continued from Part 38]

Part 39 Marijuana Medical Application Review of Clinical Studies March 19, 2015

U.S. Food and Drug Administration Center for Drug Evaluation and Research (FDA/CDER) Controlled Substance Staff (CSS).

The Medical Application of Marijuana: A Review of Published Clinical Studies March 19, 2015 Prepared by: U.S. Food and Drug Administration Center for Drug Evaluation and Research (FDA/CDER) Controlled Substance Staff (CSS) introduction and methods.

Food and Drug Administration                       FDA March page 1      March 19, 2015

The Medical Application of Marijuana: A Review of Published Clinical Studies

Table of Contents
1. Introduction………………………………….… 7

2. Methods………………………………………….. 9

2.1 Define the Objective of the Review……….-……………………………..9

2.2 Define “Marijuana” ……………………….9

2.3 Define “Adequate and Well-Controlled Clinical Studies”………10

2.4 Search Medical Literature Databases and Identify Relevant Studies …………………………….10

2.5 Review and Analyze Qualifying Clinical Studies………………….13

3. Results and Discussion……………..……. 13

3.1 Neuropathic Pain…………………………13

3.1.1 Neuropathic Pain Associated with HIV-Sensory Neuropathy ……….13

3.1.2 Central and Peripheral Neuropathic Pain……………………………………17

3.2 Appetite Stimulation in HIV …………21

3.3 Spasticity in Multiple Sclerosis…………………………………………..24

3.4 Asthma………………………………………25

3.5 Glaucoma …………………………………..27

3.6 Conclusions………………………………..27

3.6.1 Conclusions for Chronic Neuropathic Pain…………………………….28

3.6.2 Conclusions for Appetite Stimulation in HIV …………………………28

3.6.3 Conclusions for Spasticity in M$………………………………………….28

3.6.4 Conclusions for Asthma……………………,………………………………..28

3.6.5 Conclusions for Glaucoma …………….29

3.7 Design Challenges for Future Studies ………………………………….29

3.7.1 Sample Size…………………………………..29·

3.7.2 Marijuana Dose Standardization …………………………………………..30

3.7.3 Acute vs. Chronic Therapeutic Marijuana Use ……………………….31

3.7.4 Smoking as a Route of Administration …………………………………..32

3.7.5 Difficulty in Blinding of Drug Conditions ……………………………..32

3.7.6 Prior Marijuana Experience ……………33

3.7.7 Inclusion and Exclusion Criteria…………………………………………..34

3.7.8 Number of Female Subjects……………35

Appendix (Tables)…………………………….. 39  [Excluded]

[FDA March page 2 ]

List of Figure
Figure 1: Identification of Studies from PubMed Search ……………………………………. 12

List of Tables

Table I: Randomized, controlled, double-blind trials examining smoked marijuana in treatment of neuropathic pain ………………………………………………………………………………. 39

Table 2: Randomized, controlled, double-blind trials examining smoked marijuana in treatment of appetite stimulation in HIVIAIDS ……….;…………………………………………….. 44

Table 3: Randomized, controlled, double-blind trails examining smoked marijuana in treatment of spasticity in Multiple Sclerosis…………………………………………………………..: 47

Table 4: Randomized, controlled, double-blind trails examining smoked marijuana in treatment of intraocular pressure in Glaucoma ……………………………………………………….. 48

Table 5: Randomized, controlled, double-blind trails examining smoked marijuana in treatment of asthma….,………………………………………………………………………………………… 49

[FDA March page 3]

Executive Summary

Marijuana is a Schedule I substance under the Controlled Substances Act. Schedule I indicates a high potential for abuse, no currently accepted medical use in the United States, and a lack of accepted safety for use under medical supervision. To date, marijuana has not been subject to an approved new drug application that demonstrates its safety and efficacy for a specific indication under the Federal Food, Drug, and Cosmetic Act.

Nevertheless, as of October 2014, twenty-three states and the District of Columbia have passed state-level medical marijuana laws that allow for marijuana use within that state; similar bills are pending in other states.

The present review was undertaken by the Food and Drug Administration (FDA) to analyze the clinical studies published in the medical literature investigating the use of marijuana in any therapeutic areas. First, we discus sthe context fort his scientific review. Next, we describe the methods used in this review to identify adequate and well-controlled studies evaluating the safety and efficacy of marijuana for particular therapeutic uses.

The FDA conducted a systematic search for published studies in the medical literature that meet the described criteria for study design and outcome measures prior to February 2013. While not part of our systematic review, we have routinely continued to follow the literature beyond that date for subsequent studies. Studies were considered to be relevant to this review if the investigators administered marijuana to patients with a diagnosed medical condition in a well­ controlled, double-blind, placebo-controlled clinical trial. Of the eleven studies that met the criteria for review, five different therapeutic areas were investigated:

• Five studies examined chronic neuropathic pain.
• Two studies examined appetite stimulation in human immunodeficiency virus (HIV) patients.
• Two studies examined glaucoma.
• One study examined spasticity and pain in multiple sclerosis (MS).
• One study examined asthma.

For each of these eleven clinical studies, information is provided regarding the subjects studied, the drug conditions tested (including dose and method of administration), other drugs used by subjects during the study, the physiological and subjective measures collected, the outcome o f these measures comparing treatment with marijuana to placebo, and the reported and observed adverse events. The conclusions drawn by the investigators are then described, along with potential limitations of these conclusions based on the study design. A brief

[FDA page 4 March]

summary of each study’s findings and limitations is provided at the end of the section.

The eleven clinical studies that met the criteria and were evaluated in this review showed positive signals that marijuana may produce a desirable therapeutic outcome, under the specific experimental conditions tested. Notably, it is beyond the scope of this review to determine whether these data demonstrate that marijuana has a currently accepted medical use in the United States. However, this review concludes that these eleven clinical studies serve as proof-of-concept studies, based on the limitations of their study designs, as described in the study summaries. Proof-of-concept studies provide preliminary evidence on a proposed hypothesis regarding a drug’s effect. For drugs under development, the effect often relates to a short-term clinical outcome being investigated. Proof-of-concept studies serve as the link between preclinical studies and dose ranging clinical studies. Therefore, proof-of-concept studies are not sufficient to demonstrate efficacy of a drug because they provide only preliminary information about the effects of a drug. However, the studies reviewed produced positive results, suggesting marijuana should be further evaluated as an adjunct treatment for neuropathic pain, appetite stimulation in IDV patients, and spasticity in MS patients.

The main limitations identified in the eleven studies testing the medical applications of marijuana are listed below:

The small numbers of subjects enrolled in the studies, which limits the statistical analyses of safety and efficacy.

The evaluation of marijuana only after acute administration in the studies, which limits the ability to determine efficacy following chronic administration.

The administration of marijuana typically through smoking, which exposes ill patients to combusted material and introduces problems with determining the doses delivered.

The potential for subjects to identify whether they received marijuana or placebo, which breaks the blind of the studies.

The small number of cannabinoid-naive subjects, which limits the ability to determine safety and tolerability in these subjects.

The low number of female subjects, which makes it difficult to generalize the study findings to subjects of both genders.

Thus, this review discusses the following methodological changes that may be . made in order to resolve these limitations and improve the design of future studies which examine the safety and efficacy o f marijuana for specific therapeutic indications:

[FDA Page 5 March]

Determine the appropriate number of subjects studied based on recommendations in various FDA [FOOD AND DRUG ADMINISTRATION] guidances for industry regarding the conduct of clinical trials for specific medical indications.

Administer consistent and reproducible doses of marijuana based on recommendations in FDA’s 2004 guidance for industry entitled Botanical

1

The Medical Application of Marijuana: A Review of Published Clinical Studies

Drug Products.

Evaluate the effects of marijuana under therapeutic conditions following both acute and chronic administration.

Consider alternatives to smoked marijuana (e.g., vaporization).

Address and improve, whenever possible, the difficulty in blinding of marijuana and placebo treatments in clinical studies.

Evaluate the effect of prior experience with marijuana with regard to the safety and tolerability of marijuana.

Strive for gender balance in the subjects used in studies.

In conclusion, the eleven clinical studies conducted to date do not meet the criteria required by the FDA [FOOD AND DRUG ADMINISTRATION] to determine if marijuana is safe and effective in specific therapeutic areas. However, the studies can serve as proof-of-concept studies and support further research into the use of marijuana in these therapeutic indications. Additionally, the clinical outcome data and adverse event profiles reported in these published studies can beneficially inform how future research in this area is conducted. Finally, application of the recommendations listed above by investigators when designing future studies could greatly improve the available clinical data that can be used to determine if marijuana has validated and reliable medical applications.

1 This guidance is available on the internet at http://www.fda.gov/Drugs/default.htm under Guidance

(Drugs).

[FDA PAGE 6 March]

1. Introduction

In response to citizen petitions submitted to the Drug Enforcement Administration (DEA) requesting DEA to reschedule marijuana, the DEA Administrator requested that the U.S. Department of Health and Human Services (HHS) provide a scientific and medical evaluation of the available information and a scheduling recommendation for marijuana, in accordance with 21 U.S.C. 811 (b).

[Ed. Petitions were submitted in 2011 to the DEA, by Governors Chafee of Rhode Island and Gregoire of Washington, to repeal rules placing Marijuana in Schedule I of the Controlled Substance Act, contending it is accepted and safe for medical use, with low abuse potential. The DEA Administrator requested HHS evaluate scientific and medical information with recommendations. The Secretary HHS, Controlled Substance Staff, Center for Drug Evaluation and Research, FDA replied to the DEA in 2015.]

The Secretary of HHS is required to consider in a scientific and medical evaluation eight factors determinative of control under the Controlled Substance Act (CSA).

Administrative responsibilities for evaluating a substance for control under the

CSA are performed by the Food and Drug Administration (FDA), with the concurrence of the National Institute on Drug Abuse (NIDA). Part of this evaluation includes an assessment of whether marijuana has a currently accepted medical use in the United States. This assessment necessitated a review of the available data from published clinical studies to determine whether there is adequate scientific evidence of marijuana’s effectiveness. ·

Under Section 202 of the CSA, marijuana is currently controlled as a Schedule I substance (21 U.S.C. § 812). Schedule I includes those substances that have a high potential for abuse, have no currently accepted medical use in treatment in the United States, and lack accepted safety for use under medical supervision (21 U.S.C. § 812(b)(1)(A)-(C)). .

A drug product which has been approved by FDA for marketing in the United States is considered to have a “currently accepted medical use.” Marijuana is not an FDA-approved drug product, as a New Drug Application (NDA) or Biologics License application (BLA) for marijuana has not been approved by FDA. However, FDA approval of an NDA is not the only means through which a drug can have a currently accepted medical use in the United States.

In general, a drug may have a “currently accepted medical use” in the United States if the drug meets a five-part test. Established case law (Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994)) upheld the Administrator of DEA’s application of the five-part test to determine whether a drug has a “currently accepted medical use.” The following describes the five elements that characterize “currently

2 accepted medical use” for a drug :

[footnote 2 57 FR 10499, 10504-06 (March 26, 1992).]

1. the drug’s chemistry must be known and reproducible

“The substance’s chemistry must be scientifically established to permit it to be reproduced into dosages which can be standardized. The listing of the substance in a current edition of one of the official compendia, as defined by section 201(j)

[FDA page 7 March]

Medical Application of Marijuana: A Review of Published Clinical Studies

Of the Food, Drug and Cosmetic Act, 21 U.S.C. 3210), is sufficient to meet this requirement.”

1. there must be adequate safety studies

“There must be adequate pharmacological and toxicological studies, done by all methods reasonably applicable, on the basis of which it could fairly and responsibly be concluded, by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, that the substance is safe for treating a specific, recognized disorder.”

iii. there must be adequate and well-controlled studies proving efficacy

“There must be adequate, well-controlled, well-designed, well­ conducted, and well-documented studies, including clinical investigations, by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, on the basis of which it could be rarely and responsibly concluded by such experts that the substance will have the intended effect in treating a specific, recognized disorder.”

1. iv. the drug must be accepted by qualified experts

“The drug has a New Drug Application (NDA) approved by the Food and Drug Administration, pursuant to the Food, Drug and Cosmetic Act, 21 U.S.C. 355. Or, a consensus of the national community of experts, qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, accepts the safety and effectiveness of the substance for use in treating a specific, recognized disorder. A material conflict of opinion among experts precludes a finding of consensus.” and

1. the scientific evidence must be widely available.

“In the absence of NDA approval, information concerning the chemistry, pharmacology, toxicology, and effectiveness of the substance must be reported, published, or otherwise widely available, in sufficient detail to permit experts, qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, to fairly and responsibly conclude the substance is safe and effective for use in treating a specific, recognized disorder.”

One way to pass the five-part test for having a “currently accepted medical use” is through submission of an [NEW DRUG APPLICATION] NDA or [BIOLOGICS LICENSE APPLICATION] BLA which is approved by FDA. However,

[FDA page 8 March]

Application of Marijuana: A Review of Published Clinical Studies

FDA [FOOD AND DRUG ADMINISTRATION] approval of an NDA or BLA is not required for a drug to pass the five-part test.

This review focuses on FDA’s analysis of one element of the five-part test for determining whether a drug bas a “currently accepted medical use.” Specifically, the present review assesses the 3rd criterion that addresses whether marijuana has “adequate and well-controlled studies proving efficacy.” Thus, this review evaluates published clinical studies that have been conducted using marijuana in subjects who have a variety of medical conditions by assessing the adequacy of the summarized study designs and the study data. The methodology for selecting the studies that were evaluated is delineated below.

FDA [FOOD AND DRUG ADMINISTRATION]’s evaluation and conclusions regarding the remaining four criteria for whether marijuana has a “currently accepted medical use,” as well as the eight factors pertaining to the scheduling of marijuana, are outside the scope of this review. A detailed discussion of these factors is contained in FDA’s scientific and medical evaluation of marijuana.

2. Methods

The methods for selecting the studies to include in this review involved the following steps, which are described in detail in the subsections below:

1. Define the objective of the review,
2. Define “marijuana” in order to facilitate the medical literature search for

studies that administered the substance,

3. Define “adequate and well-controlled studies” in order to facilitate the

search for relevant data and literature,

4. Search medical literature databases and identify relevant adequate and

well-controlled studies, and

5. Review and analyze the adequate and well-controlled clinical studies to

determine if they demonstrate efficacy of marijuana for any therapeutic indication.

2.1 Define the Objective of the Review

The objective of this review is to assess the study designs and resulting data from clinical studies published in the medical literature that were conducted with marijuana (as defined below) as a treatment for any therapeutic indication, in order to determine if they meet the criteria of “adequate and well-controlled studies proving efficacy.”

2.2 Define.“Marijuana”

In this review, the term “marijuana” refers to the flowering tops or leaves of the Cannabis plant. There were no restrictions on the route of administration used for marijuana in the studies.

[FDA page 9 March]

Medical Application of Marijuana: A Review of Published Clinical Studies

Studies which administered individual cannabinoids (whether experimental substances or marketed drug products) or marijuana extracts were excluded from this review. Additionally, studies of administered neutral plant material or placebo marijuana (marijuana with all cannabinoids extracted) that had subsequently been supplemented by the addition of specific amounts of tetrahydrocannabinol (THC) or other cannabinoids were also excluded (Chang et al., 1979).

2.3 Define uAdequate and Well-Controlled Clinical Studies”

The criteria for an “adequate and well-controlled study” for purposes of determining the safety and efficacy of a human drug is defined under the Code of Federal Regulations (CFR) in 21 CFR 314.126. The elements of an adequate and well-controlled study as described in 21 CFR 314.126 can be summarized as follows: .

1. The main objective must be to assess a therapeutically relevant outcome.
2. The study must be placebo-controlled.
3. The subjects must qualify as having the medical condition being studied.
4. The study design permits a valid comparison with an appropriate control

condition.

5. The assignment of subjects to treatment and control groups must be

randomized.

6. There is minimization of bias through the use of a double-blind study

design.

7. The study report contains a full protocol and primary data.
8. Analysis of the study data is appropriately conducted.

As noted above, the current review examines only those data available in the public domain and thus relies on clinical studies published in the medical . literature. Published studies by their nature are summaries that do not include the level of detail required by studies submitted to FDA in an NDA.

While the majority of the elements defining an adequate and well-controlled study can be satisfied through a published paper (elements #1-6), there are two elements that cannot be met by a study published in the medical literature: element #7 (availability of a study report with full protocol and primary data) and element #8 (a determination of whether the data analysis was appropriate). Thus, for purposes of this review, only elements #1-6 will be used to qualify a study as being adequate and well-controlled.

2.4 Search Medical Literature Databases and Identify Relevant Studies

[FDA page 10 March]

We identified randomized, double-blind, placebo-controlled clinical studies conducted with marijuana to assess marijuana’s efficacy in any therapeutic indication. Two primary medical literature databases were searched for all studies

1. [3 While not a systematic review, we have followed the recent published literature on marijuana use for possible therapeutic purposes and, as of January 2015, we found only one new study that would meet our criteria (Naftali et al., 2013). This study examined the effects of smoked marijuana on Crohn’s ]

3 posted to the databases prior to February 2013 :

• PubMed: PubMed is a database of published medical and scientific studies that is maintained by the U.S. National Library of Medicine (NLM) at the National Institute o f Health (NIH) as a part of the Entrez system of information retrieval. PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books (http://www.ncbi.nlm.nih.gov/pubmed).
• gov: ClinicalTrials.gov is a database of publicly and privately supported clinical studies that is maintained by the NLM. Information about the clinical studies is provided by the sponsor or Principal Investigator of the study. Information about the studies is submitted to the website (“registered”) when the studies begin, and is updated throughout the study. In some cases, results of the study or resulting publication citations are submitted to the website after the study ends (https:/Iclinicaltrials.govIct2/about-site/background).

ClinicalTrials.gov was searched for all studies administering marijuana. The results of this search were used to confirm that no completed studies with published data were missed in the literature search. During the literature search, references found in relevant studies and systematic reviews were evaluated for additional relevant citations. All languages were included in the search. The

4

PubMed search yielded a total of 566 abstracts.

1. [4 The following search strategy was used, “(cannabis OR marijuana) AND (therapeutic use OR therapy) AND (RCT OR randomized controlled trial OR “systematic review” OR clinical trial OR clinical trials) NOT (“marijuana abuse”[Mesh] OR addictive behavior OR substance related disorders)”. ]

review was conducted with 85 papers to assess eligibility. From this evaluation, only 11 of 85 studies met the 6 CFR elements for inclusion as adequate and well­ controlled studies.

Figure 1 (below) provides an overview of the process used to identify studies from the PubMed search. The eleven studies reviewed were published between 1974 and 2013. Ten of these studies were conducted in the United States and one study was conducted in Canada. These eleven studies examined the effects of smoked and vaporized marijuana for the indications o f chronic neuropathic pain, spasticity related to multiple sclerosis (MS), appetite stimulation in patients with human immunodeficiency virus (HIV), glaucoma, and asthma. All included studies used adult patients as subjects. All studies conducted in the United States

[FDA Page 12 March]

were conducted under an investigational new drug (IND) as Phase 2 investigations.

Figure 1: Identification of Studies from PubMed Search

27 Administered delta 9-THC

20 Administered marijuana plant extracts 4 Administered Cannabidiol
4 Administered hemp seed oil

I Administered Rimonabant • 6 Were mechanistic studies
7 Had a primary focus on safety

76 Excluded 63 Administered individual cannabinoids or marijuana plant derived products

l9 Articles from the PubMed search meet inclusion criteria I
“Articles were deemed irrelevant if they examined safety or adverse event related outcomes,

including psychoactive effects or other adverse events. excluded article types included

0

comments, reviews, meta-analyses, and news articles.
Cannabinoids administered included synthetic cannabinoids. “Rimonabant is a cannabinoid receptor antagonist. An additional 2 studies meeting the inclusion criteria were found through the reference search:

Two qualifying studies, which assessed marijuana for glaucoma, were previously reviewed in the 1999 Institute of Medicine (IOM) report entitled “Marijuana and Medicine Assessing The Science base

[5 footnote 5 In January 1997, the White House Office of National Drug Control Policy (ONDCP) requested that the IOM conduct a review of the scientific evidence to assess the potential health benefits and risks of marijuana and its constituent cannabinoids. Information for this study was gathered through scientific workshops, site visits to cannabis buyers’ clubs and HIVIAcquired Immunodeficiency Syndrome (AIDS) clinics, analysis of the relevant scientific literature, and extensive consultation with biomedical and social scientists The report was finalized and published ill 1999 .]

We did our own analysis of these two studies and concurred with the conclusions in the IOM report. Thus, a detailed discussion of the two glaucoma studies is not included in the present review. The present review only discusses 9 of the identified 11 studies. For a summary of the study design for all 11 qualifying studies, see Tables 1-5 (located in the Appendix).

[FDA page 12 March]

Medical Application o f Marijuana: A Review o f Published Clinical Studies

Based on the selection criteria for relevant studies described in Section 2.3 (“Define ‘Adequate and Well-Controlled Clinical Studies”‘), a number of clinical studies that investigated marijuana, as defined in this review, were excluded from this review. Studies that examined the effects of marijuana in healthy subjects were excluded because they did not test a patient population with a medical condition (Flom et al., 1975; Foltin et al., 1986; Foltin et al., 1988; Hill et al., 1974; Milstein et al., 1974; Milstein et al., 1975; Soderpalm et al., 2001; Wallace et al., 2007; Greenwald and Stitzer, 2000). A 1975 study by Tashkin et al. was excluded because it had a single-blind, rather than double-blind, study design. Two other studies were excluded because the primary outcome measure assessed safety rather than a therapeutic outcome (Greenberg et al., 1994; Abrams et al., 2003).

2.5 Review and Analyze Qualifying Clinical Studies

Qualified clinical studies that evaluated marijuana for therapeutic purposes were examined in terms of adequacy of study design including method of drug administration, study size, and subject inclusion and exclusion criteria. Additionally, the measures and methods of analysis used in the studies to assess the treatment effect were examined.

[continued Part 40]

Abbreviations

Addiction Research Center Inventory (ARCI)

adenosine triphosphate (ATP)

adrenocorticotropic hormone (ACTH),

biologics license application (BLA)

cannabinoid receptor type 1 (CB1)

cannabichromene (CBC)

cannabidiol (CBD)

cannabinol (CBN)

Conditioned place preference (CPP)

Controlled Substances Act (CSA)

Controlled Substance Staff, Center for Drug Evaluation and Research, FDA

delta 9-THC

Diagnostic and Statistical Manual (DSM-5)

Drug Abuse Warning Network (DAWN) SAMHSA

Emergency Department [ED]

FDA Center for Drug Evaluation and Research

Food and Drug Administration (FDA)

U.S. Department of Health and Human Services (HHS)

International Classification of Diseases (ICD-10

[Investigational new drug] IND

IQ Intelligence Quotient

Monitoring the Future (MTF) survey

National Institutes of Health’s National Institute on Drug Abuse (NIH/NIDA)

[National Survey on Drug Use and Health] (NSDUH)

[new drug application] NDA

NMDA antagonists; N-Methyl-D-aspartate -anesthetics that antagonize, or inhibit the action

Substance Abuse and Mental Health Services Administration (SAMHSA)

System to Retrieve Information from, Drug Evidence (STRIDE) DEA’s

tetrahydrocannabinol (THC)

Treatment Episode Data Set (TEDS) 2011

[Continued next Part 40]

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