A02 - SOW.docx

Statement of Work

Evaluation of Abuse Potential of Synthetic Cannabinoids and Phytocannabinoids Using In Vivo Pharmacological Studies I. Background

The Drug Enforcement Administration’s (DEA) Diversion Control Division (DC), Drug and Chemical Evaluation Section (DPE) is responsible for evaluating drugs and chemicals to determine whether these substances have abuse potential. These evaluations are used by DEA to support its domestic scheduling activities. In order for DEA to determine the abuse potential of drugs and chemicals, pharmacological, medical, epidemiological, and other scientific data for these drugs, when necessary, are needed to initiate the administrative procedure to place these substances under regulatory control according to the guidelines of the Controlled Substances Act (CSA).

Recently, numerous novel psychoactive substances (NPS) to include synthetic cannabinoid and phytocannabinoid compounds have emerged within the United States and poses significant risk to the public safety. Numerous NPS have been identified in samples submitted to federal, state and local forensic laboratories. There have been reports of overdoses, including fatalities, associated with the abuse these substances. In response to the associated public health threat with the abuse of NPS, the Administrator of DEA has placed several NPS in Schedule I of the CSA under a temporary scheduling order to avoid an imminent hazard to the public safety. Preliminary studies (in vitro) have shown that these substances share pharmacological similarities with other known drugs of abuse. Further, there are emerging NPS with paucity of pharmacology data. Detailed information on many NPS biological and pharmacological activities is limited.

II. Brief description of work

For this project, unless otherwise specified by the DEA representative, the vendor shall purchase the reference drugs and all test substances[footnoteRef:1] approved by the DEA for testing. The DEA will provide the test substances otherwise not commercially available to the potential vendor for the requested testing. Some of these substances are Schedule I substances. Therefore, the vendor should already have a Schedule I researcher registration with DEA. The vendor shall conduct appropriate preclinical studies such as locomotor activity study, cannabinoid tetrad study, and drug discrimination study on these substances in comparison to appropriate controls and reference standard substances. The type of study requested is dependent upon the class of substance. The reference training drugs shall include, but not be limited to THC (Δ9-tetrahydrocannabinol, and other drugs as directed by the DEA representative. Each substance shall be assessed for its abuse potential by using appropriate studies in rodents. The vendor will provide the DEA with investigational study results and a description of the methodology used to conduct the investigation in the form of a study report based on the timeline specified in this statement of work (SOW), if not earlier. If a report on all requested studies cannot be provided by the specified timelines, a letter stating the anticipated date of completion of investigations and anticipated delivery of a study report will be required prior to that date. Final study conditions, including but not limited to the number of rodent, or the strain of rodent used, shall be subject to approval of the DEA representative. The vendor shall be able to conduct all studies though not all assays might be requested. [1: The vendor shall provide adequate information on the purity of the test substance before conducting pharmacological testing. Also, should the drug cost exceed $500, the vendor shall contact DEA representative for approval.]

III. Specific requirements

Task 1. Drug source, storage and recordkeeping.

I. Drug Source: Unless otherwise specified by the DEA representative (if it is determined that the test substance is not commercially available), the vendor shall purchase the reference and test drugs[footnoteRef:2]. The cost of the drug should not exceed $500. If there is a deviation, DEA representative should be notified immediately. Actual cost of drug can be billed as an invoice. The vendor shall conduct a preclinical evaluation of these test substances (as specified in tasks listed below) in comparison to appropriate controls and the appropriate reference standard. Pharmacological evaluation of each test substance shall be done using appropriate in vivo assays as approved by DEA. [2: The vendor shall provide adequate information on the purity of the test substance before conducting pharmacological testing.]

II. Record Keeping: The vendor shall maintain electronic and paper copies of a chronological log of the test substance receipt and evaluation using Microsoft Excel spreadsheet software. When each substance is received, the following shall be recorded:

a) test substance's name;

b) source of the test substance (if it is a purchased or a standard substance);

c) purity of the test substance (all test and reference drug should be ≥ 98%);

d) date testing of the test substance was authorized;

e) date the test substance was received (If provided by the DEA);

f) amount of test substance received (if provided by the DEA);

g) pharmacological studies authorized by DEA for the test substance (e.g. locomotor activity and drug discrimination);

h) date when the study began for each authorized study;

i) amount of test substance used for each authorized study;

j) date when the study was completed for each authorized study;

k) date when the report was sent to the DEA.

This cumulative Receipt and Evaluation log shall be kept up to date and forwarded to the DEA representative upon request.

III. Drug Storage and Schedule I Researcher Registration Requirement: Some of the test substances maybe in Schedule I of the CSA. Under these circumstances, it is required that the test substances be stored under Schedule I requirements as specified by the CSA and that the vendor evaluating the test substances shall be registered with the DEA as a Schedule I researcher. Some reference drugs are in Schedule II of the CSA. Therefore appropriate DEA license and storage requirement shall be maintained. In cases where test substances are not Schedule I, drug storage requirements shall be maintained under Good Laboratory Practices (GLP) or GLP-like conditions.

Task 2. Protocols of in vivo pharmacological studies (locomotor activity, cannabinoid tetrad studies, drug discrimination studies and other optional studies (e.g. head twitch response)) in laboratory rodent animals

General protocols that are used for in vivo locomotor activity and drug discrimination studies shall be provided by the vendor to the DEA. The protocols shall contain a description of the methodology used to conduct the investigation, a description of the apparatuses that will be used for conducting the studies, maintenance of the animals to be used in the tests, procedures for analysis of the data including proposed statistical methods, and proposed presentations of the data and study results. Specifically, the study protocol should conform to the following standards:

I. A study protocol shall be provided for each individual in vivo pharmacological study. For example, one protocol should be provided for locomotor activity and one protocol for drug discrimination study, etc.

II. The study protocols must be specifically written to meet the protocol preferences as listed in this SOW under Tasks 3, 4, 5 and 6.

III. The study protocol should closely follow the format of the materials and methods section that would be submitted for a peer-reviewed journal article. Details including the animal strain, number of animal, animal care, experimental design, data analysis including statistical methods and generation of results (e.g. ED50 and 95% confidence limit values, repeated measures ANOVA as appropriate) shall be included.

IV. The study protocol shall include examples of how data will be presented. For example, representative dose-response curves, tables, and statistical analyses should be included. This information can be taken from previously published studies. However, this information should be included in a section as part of the study protocol and shall not be submitted as a separate file, but the data should be cited (i.e. submitting the example paper with the study protocol would not be considered acceptable).

V. Signature lines shall be included on each study protocol. Upon approval of the protocol by DEA and the vendor, the protocol will be signed by each representative. The original signed document will remain with DEA. A copy of the signed protocol will be provided to the vendor. The signed protocols will serve as an official record.

Following receipt of the standard protocols by the DEA representative, a phone conversation may be scheduled to discuss the study protocols and SOPs. Any significant deviations or modifications from the protocol by the vendor must be authorized by DEA. The vendor must provide a modified protocol (e.g., change in time points, change in vehicle used, modification needed based on a specific test substance, etc.), the amended or modified protocol must be submitted in writing to the DEA representative for review and approval. The DEA representative must approve work with each new assay modifications.

NOTE: The DEA representative must approve work with each new test method prior to its initiation. Only those test substance specified by the DEA shall be evaluated in the new study under development. For the most part, standard substances (known drugs of abuse such as THC and others) shall be used. Special reports and data summaries shall adhere to a format determined by the DEA.

Task 3. Evaluation of test substances in the in vivo locomotor activity study

I. Objective: Using the general protocol agreed to by the vendor and DEA in Task 2, the vendor shall, as specified by the DEA representative, evaluate standard (reference) and/or test substances using the in vivo locomotor activity assay. The goal of this in vivo pharmacological study (locomotor activity study) is to determine whether the test substance can elicit changes in locomotor activity of the rodent. Further, this study can be used to identify parameters to include but not limited to onset of action, time to peak effect, duration of action, and dose effect response before conducting other behavioral tests for the test substances.

II. Experimental Design: Locomotor activity assays shall be conducted in mice unless otherwise agreed upon by both the DEA and vendor. If alternative rodent animal species or alternate species are selected, the vendor will provide to the DEA a comprehensive rationale for selecting a different animal species. The DEA and the vendor shall agree on the strain of rodent to be used for each of the studies. Briefly, locomotor activity test will be conducted in an automated activity monitoring chamber located in a sound-attenuating device that provides dim illumination. Prior to testing, mice will be injected via appropriate route with either vehicle or reference substances or test substance and immediately placed in the chamber for locomotor activity monitoring. In all studies, horizontal activity (interruption of photocell beams) reported as horizontal activity count will be measured. Testing shall be conducted with one mouse per activity chamber. Experimental groups for evaluating each test substance should consist of appropriate number of doses (three experimental doses at a minimum) using a pharmacologically effective dose range to generate a dose response curve, and a statistically appropriate number of animals per group (at least 8 animals). Appropriate controls shall be used. For each test substance, ED50 (50% effective dose) and 95 % confidence limit values shall be calculated. Data on dose-response curves shall also be presented and reported.

III. Potential Experimental Issues and Reporting: In the event that any experimental issues arise (e.g., inability to dissolve test compound, unexpected results, animal lethality, deviation or departure from the agreed protocol, statistics issue due to experimental constrains), the vendor shall immediately notify the DEA representative, in writing (email) with the issue and if the issue was resolved. Based on the issue noted by the vendor, the DEA representative may schedule a phone conversation or respond by email. All experimental issues that arise and the resolutions shall be documented in writing even if the issue and resolutions are discussed in a phone conversation.

IV. Study Report: Following completion of the in vivo locomotor activity study for each test substance, the results in the form described in Task 8 (e.g. ED50 and 95% confidence limit values, dose response curves) shall be provided to the DEA representative for review and acceptance. The DEA representative may contact the vendor if there are any notable issues with the results.

Task 4. Evaluation of test substances in the in vivo cannabinoid tetrad testing battery.

I. Objective: The goal of this study is to evaluate the effects of test substances on antinociception, body temperature, spontaneous locomotor activity, and catalepsy. Using the general protocol with agreement of the vendor and DEA in Task 2, the investigators shall, as specified by the DEA representative, evaluate standard (reference e.g. THC) and/or test substances using the agreed upon in vivo tetrad testing battery.

II. Experimental Design: The in vivo tetrad testing battery shall be conducted in mice unless otherwise agreed upon by both the DEA and vendor. The vendor shall provide justification for the type of strain selected to conduct this study. Test substances selected for the tetrad test battery shall not be included as a test substance in Tasks 3 (in vivo locomotor activity test) unless otherwise specified by the DEA representative. Selection of the positive and/or negative control, if required, for each test substance selected for the tetrad testing battery shall be specified by DEA to vendor. Experimental groups for evaluating each test substance should consist of appropriate number of doses (three experimental doses at a minimum), using a pharmacologically-effective dose range to generate a dose response curve, and a statistically appropriate number of animals per group (at least 8 animals). Appropriate controls shall be used. For each active test substance, ED50 (50% effective dose) and 95% confidence limit values shall be calculated. Data on dose-response curves shall also be presented and reported.

III. Potential Experimental Issues and Reporting: In the event that any experimental issues arise (e.g. inability to dissolve test compound, unexpected results, animal lethality, deviation or departure from the agreed protocol, statistics issue due to experimental constrains), the vendor shall immediately notify the DEA representative, in writing (email) with the issue and if it was resolved. Based on the issue noted by the vendor, the DEA representative may schedule a phone conversation or respond by email. All experimental issues that arise and the resolutions shall be documented in writing even if the issue and resolutions are discussed in a phone conversation.

I. Study Report: Following completion of the in vivo tetrad assay for each test substance, the results in the form described in Task 8 (e.g. ED50 and 95% confidence limit values, dose response curves) shall be provided to the DEA representative for review and acceptance. The DEA representative may contact the vendor if there are any notable issues with the results.

Task 5. Evaluation of test substances in in vivo drug discrimination assay

I. Objective: The goal of this in vivo pharmacological study is to understand whether the test substances can be substituted for the discriminative-stimulus effects produced by a known drug of abuse. Using the general protocol agreed to by the vendor and DEA in Task 2, the vendor shall, as specified by the DEA representative, evaluate standard (reference) and test substances using the in vivo drug discrimination assay.

II. Experimental Design: Drug discrimination studies shall be conducted in rats unless otherwise agreed upon by both the DEA and vendor. If alternative rodent animal species or alternate species are selected, the vendor will provide to the DEA a comprehensive rationale for selecting a different animal species. The DEA and the vendor shall agree on the strain of rodent to be used for each of the studies. The vendor shall maintain groups of animals (rats) trained to discriminate the stimulus effects of a given reference drug (from its vehicle during each year of the agreement. It is expected that drug discrimination training for the animals commence within a week after the protocol is approved. The reference training drugs shall include, but not be limited to THC and other drugs as directed by the DEA representative. The training and reference drugs should be tested periodically to establish a dose effect reference standard in the rats. The vendor shall have the equipment available for drug discrimination testing procedures such that the experiments can be conducted in a relatively expedient manner for this assay. Additionally, it is encouraged to have multiple and/or automated apparatus for evaluating the discriminative stimulus effects in order to increase efficiency of completing the experiments.

III. Potential Experimental Issues and Reporting: In the event that any experimental issues arise (e.g. inability to dissolve test compound, unexpected results, animal lethality, deviation or departure from the agreed protocol, statistics issue due to experimental constrains ), the vendor shall immediately notify the DEA representative, in writing (email) with the issue and if the issue was resolved. Based on the issue noted by the vendor, the DEA representative may schedule a phone conversation or respond by email. All experimental issues that arise and the resolutions shall be documented in writing even if the issue and resolutions are discussed in a phone conversation.

IV. Study Report: Following completion of the in vivo tetrad assay for each test substance, the results in the form described in Task 8 (e.g. ED50 and 95% confidence limit values, dose response curves) shall be provided to the DEA representative for review and acceptance. The DEA representative may contact the vendor if there are any notable issues with the results.

Task 6. Optional In Vivo Studies

The DEA is open to the inclusion of other behavioral studies (e.g., physical dependence, conditioned place preference, rotorod assays), pharmacokinetic studies, and route of administration (e.g., inhalation) that can provide further information on the pharmacological properties of this class of substances. Please note that inability to perform any of the suggested optional studies will not exclude a researcher for consideration. If the DEA representative and the vendor agree on all matters (i.e., feasibility, cost, etc.) regarding these optional in vivo studies then these study can be added to the contract.

Task 7. Data presentation

The data organized in tables shall be provided to the DEA representative. Information should include, but not be limited to: (1) name of substance; (2) in vivo assay tested; (3) date(s) of study; (4) animal species used and source; (5) route(s) of administration, vehicle, and doses used; (6) number of animals per group; (7) observed effect at each selected dose level; and (8) calculated ED50 and 95 % confidence interval values. For instances where there is insufficient information to provide the specified information in the table, vendor will document the rationale in the table. This recordkeeping of the data and results is separate from the recordkeeping of the test substance as listed in Task 1 and also is separate from the reporting of study results listed in Tasks 3 - 5. The summarized data ("cumulative data table") shall be forwarded monthly to the DEA representative. The vendor and DEA will ensure all electronic information is accessible to individuals with disabilities in accordance with Section 508 of the Rehabilitation Act (29 U .S.C. 794d), as amended in 1998.

Task 8. Final study report for each substance tested

Following completion of the experiments in Task 3, 4, and 5, a final study report containing the complete methodology, data analysis, and study results for each test substance shall be provided in electronic format to the DEA.

1) Study Report:

i) Study Reports: A final study report containing the complete methodology, data analysis, and study results for each compound/assay shall be provided to the DEA. The DEA representative will provide an example of a Final Study Report for the vendor to use in preparation of the report. Where feasible, data shall be presented in tables and figures and the results shall be described in a textual format. Raw data should also be included in an appendix to the report. The vendor shall first submit a draft report in using Microsoft word to the DEA Representative. Upon review by the DEA Representative, revisions may need to be made. Once revisions are completed or the draft is cleared by the DEA Representative, final copies of the report shall be provided to the DEA Representative in electronic MS word version as well as a portable document file (PDF) format. Each report shall be due no later than thirty (30) calendar days after the study completion date specified in the Contractor's log of substance evaluation. The format shall be as follows:

ii) Front cover to contain: Date, title (to include compound name), researcher (name/address/phone number, email), contract number, DEA representative (name).

iii) Main body to contain: (1) A brief (one or two paragraph) summary of the findings (2) detailed methods, and (3) results organized as text, tables, and/or figures, as agreed upon with DEA representative.

Task 9. Reporting Requirements

All reports required herein shall be submitted in electronic format to the DEA representative as detailed in the following subsections. The preparation and submission of regularly recurring Technical Progress Reports will be required for this agreement. These reports shall require descriptive information about the activities undertaken during the reporting period and will require information about planned activities for future reporting periods. The frequency and specific content of these reports will be determined by the DEA Representative.

a) Monthly Reports: On or before the 5th working day of each month, the vendor shall submit one electronic copy in PDF format of a report on activities during the month. In the report, vendor shall include (1) all test substance evaluation reports completed during the month (2) a table, or set of tables, of all compounds tested in the contract, with the main results so far, and (3) entries for the compounds next in line for testing as specified above

b) Study Reports: See Task 7 for details on these reports.

c) Annual Progress Reports: On or before the 5th working day following the end of each period of performance year, the vendor shall submit a report on activities during the year. Two copies, one paper copy and one electronic copy in Microsoft Word or PDF format, shall be sent to the DEA representative. In the report, vendor shall include: section 1 – a summary of the overall results generated on all substances during the past 12 months; section 2 – a brief summary of any problems encountered while conducting the established experimental assays and, if applicable, a description of how those problems were resolved, as well as a brief summary of progress in any experimental assay development; section 3 – the log of test substance purchased, See Task 1; section 4 – any other information required. The summary of overall results (section 1) should not be an all-inclusive summary of data generated on standard substances but, rather a summary highlights.

Task 10. Level of Effort

The DEA Representatives reserve the right to visit the laboratory where testing is being conducted.

a) Meetings between DEA and vendor:

i. Monthly conference calls: The vendor and the DEA representative shall have a teleconference meeting once a month. Other DEA and contract staff may participate if necessary. These meetings may be waived at the discretion of the DEA representative. Specific items for discussion shall be subject to the approval of the DEA representative.

ii. In-person meetings: DEA representative reserves the right to visit the vendor’s facility for the purpose of site visitation. At approximately 12-month intervals, DEA representatives may set-up a meeting with the vendor for the purpose of reviewing past, current, and/or proposed work under this agreement. These meetings may be waived at the discretion of the DEA representative. Specific items for discussion shall be subject to the approval of the DEA representative.

iii. Pre-Meeting Materials: Three weeks before each meeting, the vendor shall prepare "pre-meeting packets" summarizing all data on test compounds to be presented and describing relevant assay methods. This packet shall also include summaries of: (1) proposals for optimizing existing assays; (2) progress in ongoing assay development; (3) proposals for new assay development; (4) problems encountered in implementing tasks required in the agreement; and (5) proposed solutions to problems encountered. The vendor shall deliver this information to the DEA representative at least 3 weeks in advance of the meeting for approval, and after approval has been obtained, to each consultant at least 2 weeks prior to the meeting.

iv. Post-Meeting Materials: After the meeting, the vendor shall prepare a post-Meeting report, summarizing the recommendations and comments of the attending consultants and DEA staff. The report shall include recommendations for optimizing specific assays and suggestions for incorporating new assays into the DEA testing program. The Post- Meeting Report shall be sent to the DEA representative within three (3) weeks of the meeting.

v. Meeting Location(s): The site of the meeting shall be either at the annual scientific meetings of professional associations such as the College on Problems of Drug Dependence and the Society for Neuroscience, the DEA headquarters or other locations as specified by the DEA. This agreement shall not be responsible for the payment of DEA consultants' expenses. Meetings via video teleconference to discuss status and other issues may be held, but could be cancelled at the DEA’s discretion.

IV. Period of Performance

The period of performance for this agreement shall be for 6 month duration with the option to extend for 2 additional option periods and is subject to renewal by DEA and vendor after each performance period. The exact dates of the period of performance are to be determined. If the agreement at the end of one year is terminated by one or both parties, the period of performance will no longer extend to subsequent years. Prior to shortening the period of performance, a written notification shall be provided with 90-day notice.

I. Deliverables

If a report on any of the requested studies cannot be provided by the specified timelines, the vendor must notify the DEA immediately upon obtaining this knowledge. This notification shall be followed up by a letter to the DEA stating the reason for the delay, the anticipated date of completion of investigations, and the anticipated delivery of the study.

Agreed protocols of the in vivo locomotor activity, cannabinoid tetrad study and drug discrimination assays Within 2 working days following receipt of protocol.

Initial protocols to be provided to DEA within 30 calendar days after start of the agreement period.

Modified or revised protocols to be provided to DEA for review within 7 calendar days of discussion/notification by either party that the protocol must be modified or revised.

before the expiration of the agreement period.

before the expiration of the agreement period.

II. Use of Data

All documents, data, materials, records, and information sources provided to the vendor, developed or maintained by the vendor in the performance of this contract under this SOW are deemed to be the property of the DEA. All data collected, generated, manipulated or otherwise processed under this agreement are confidential information unless or until DEA authorizes its release. None of these data may be used at any time for any purpose except to generate reports or other requirements specified in the Statement of Work, without prior written approval of the DEA. The DEA and the vendor will mutually agree to discuss matters of Freedom of Information Act (FOIA) policy before each agency independently discloses requested information.

On or before the agreement year expiration, the vendor shall deliver (or otherwise dispose per the DEA) all data, including raw databases (electronic or hard copies), tapes, software programs used to interpret or manipulate data, weight calculation files, data collection forms, file definitions, and various edited databases generated under this contract to the DEA (except for data necessary only to comply with other Federal data retention requirements, such as requirements pertaining to clinical trials or the Food and Drug Administration's rules pertaining to drug applications).

During or after the agreement, no data may be released, presented or published except upon prior approval of the DEA. All requests which the vendor will receive from third parties for access to the data must be referred to the DEA.

III. Retention of Information

The vendor shall retain, for 5 years beyond the duration of this agreement, all laboratory notebooks (which shall include paper copies of raw data) and electronic data files. Electronic data files shall be labeled and recorded in a manner that allows their association with corresponding laboratory notebook entries and paper copies of raw data. On or before the expiration date of this agreement, if so instructed by the DEA representative, the vendor investigators shall ship these items to the DEA representative in Arlington, VA.

DEA Representative (Scientific and Technical Contact):

Luli Akinfiresoye, Ph.D Pharmacologist Drug and Chemical Evaluation Section Drug Enforcement Administration

DEA/DC/DPE 10