Amendment_0001_D-17-OD-0092.pdf

Statement of Work

Evaluation of Synthetic Opioid Substances using the Warm-Water Analgesia Assay

I. Background

The Drug Enforcement Administration’s (DEA) Diversion Control Division (DC), Drug and Chemical Evaluation Section 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 synthetic substances with opioid-like activity have been abused in the United States and pose a significant risk to the public safety. Law enforcement and forensic laboratory databases have reported increased encounters of new synthetic opioid substances.

Severe consequences of synthetic opioid abuse include non-fatal overdoses and deaths. Due to the immediate public health threat associated with these synthetic opioid substances, several of them have been placed under Schedule I under a temporary scheduling order which lasts for a period of up to 3 years. In order to place synthetic opioid substances under permanent Schedule I control or to move the synthetic opioids from a temporary scheduling order to a permanent Schedule I scheduling order, pharmacological data is required.

Analgesia is a pharmacological property that is associated with opioid drugs. The analgesic effects associated with opioids and related drugs have been reported to lead to abuse of this drug class. As such, DEA would like the vendor to assess the analgesic properties of the selected synthetic opioids in an in vivo pharmacological assay. Due to the time-sensitivity of this work, DEA is requesting that the pharmacological studies be initiated and completed in an expedient manner.

II. Brief Description of Work

For this project, the DEA will provide the synthetic opioid substances to the potential vendor. Some of the compounds may be Schedule I compounds. Therefore, the vendor should already have a Schedule I researcher registration (ideal) or be in the process of obtaining a Schedule I researcher registration. The vendor shall conduct a preclinical analgesia evaluation of these substances in comparison to appropriate controls and reference standard opioid substances (e.g., morphine, fentanyl, etc.). Each compound shall be assessed for opioid receptor-mediated analgesic effects. 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. The vendor will evaluate 20 synthetic opioid substances. Upon award of the contract, the vendor will be notified of the number of substances that will be tested and the identity of these substances. The synthetic opioid substances will be provided by DEA to the vendor in quantities sufficient enough for the proposed pharmacological study. It is the vendor’s responsibility to purchase reference (control) compounds for the analgesia studies.

III. Specific Tasks to be Performed

Task 1. Protocol of in vivo Analgesia Study

The DEA Representative will provide a copy of the in vivo analgesia protocol that shall be used as a guide for the evaluation analgesic effects with the synthetic opioids. Briefly, drugs shall be administered subcutaneously (s.c.) or intraperitoneally (i.p.) into rodents (mice preferred, but rats may be used if justified by vendor). The vendor will determine the appropriate doses to administer to the rodent using their preferred method of choice and will use this information to also determine an appropriate time point to commence analgesia testing (e.g. 10 minutes after dosing). To determine analgesia, the vendor shall use a tail-immersion assay into a warm water bath. The rodent shall be restrained during the tail-immersion assay. Tails should be exposed to water baths set at temperatures that would be 1) ambient and 2) generate a pain response in untreated animals. Tail withdrawal latencies shall be measured with a cutoff time of 10 seconds.

Tail withdrawal latencies shall be measured at various time points for up to 120 minutes after injection of the test substance or its vehicle. Tail withdrawal latency shall be recorded with a stopwatch or another comparable device. Dose-effect curves (DECs) shall be generated from the tail withdrawal latency data and analyzed using standard regression techniques to derive ED50 values (50% effective dose in the DEC) with 95% confidence limits (95% CL). Each synthetic opioid substance shall be evaluated using an appropriate number of doses (at least 3 doses), an appropriate dose range to generate a DEC, and a statistically appropriate number of animals per group (N≥8 animals per dose group). A phone discussion may be scheduled to discuss the specifics of the protocol and vendor capabilities with respect to the protocol. Any significant deviations or modifications from the protocol by the vendor must be authorized by DEA. The vendor must provide a modified protocol, in writing, to the DEA representative for any deviations or modifications deemed significant by DEA.

Deliverables:

1. DEA representative shall provide a protocol of the in vivo analgesia study.

2. Vendor shall provide modified protocol, in writing, if there are significant deviations or modifications.

Timeline:

1. A phone call shall be scheduled within 2 working days following receipt of protocol.

2. A modified protocol shall be provided to DEA by vendor within 5 working days following phone call.

Task 2. Evaluation of Test Compounds in In Vivo Analgesic Effects in Laboratory Rodent Animals

For Schedule I compounds, the vendor should already have a Schedule I researcher registration (ideal) or be in the process of obtaining a Schedule I researcher registration and subsequently submit their approved protocol to DEA for Schedule I protocol review. Since several compounds (unscheduled and Schedule I) may be submitted, the vendor shall commence studies for compounds that are currently not scheduled and then start studies with Schedule I compounds upon completion and approval of the Schedule I protocol review. The vendor shall consult with the DEA representative with respect to the priority of substances to be tested. The vendor shall follow the DEA-approved in vivo analgesia protocol for conducting these studies.

Studies should ideally commence immediately after approval of the protocol for unscheduled compounds and approval of the Schedule I protocol review for Schedule I compounds. The vendor shall have the equipment available for analgesia testing procedures for the warm-water tail assay such that the experiments can be conducted in an expedient manner. Additionally, it is encouraged to use dosing methods, such as cumulative dosing, and having multiple and/or automated apparatus for evaluating the analgesic effects to increase efficiency of completing the experiments. Reference compounds (e.g. morphine, fentanyl) shall be purchased by the vendor.

Test compounds will be provided by the DEA to the vendor.

In addition to determining the analgesic effects of the synthetic opioid compounds, it is imperative to evaluate the analgesic effects in the presence of the appropriate antagonist(s) as listed in the protocol from Task 1. In the event that any experimental issues arise (e.g. inability to dissolve test compound, unexpected results, animal lethality), 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.

The vendor shall provide monthly progress reports to the DEA representative in writing.

The progress reports shall contain, but not be limited to, 1) compounds evaluated, 2) brief description of results (ED50), 3) compounds to be evaluated, 4) doses to be evaluated and any other relevant information.

Deliverables:

1. Monthly progress reports which provide detailed status and document any issues encountered or anticipated.

2. Results of the synthetic opioid compounds evaluated in the in vivo analgesic effect studies, as those findings are determined.

3. Based on the performance efficiency, the vendor is expected to communicate with and provide to DEA the major findings of any study immediately following the completion of any study on any test substance.

Timeline: 90 calendar days from completion of and DEA acceptance of Task 1.

Task 3. Final Study Report For Each Synthetic Opioid Substance

Following completion of the experiments in Task 2, a final study report containing the complete methodology, data analysis, and study results for each compound 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.

Deliverable: Final Study Report for each synthetic opioid substance

Timeline: 7 calendar days from completion of analgesia study for the respective synthetic opioid substance.

I. Period of Performance As outlined in this SOW, the period of performance for the Statement of Work shall be from August 1, 2017 – February 1, 2018 based on the timelines provided for the deliverables for each task.

II. 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.

TASK

NUMBER

DELIVERABLE DELIVERY

SCHEDULE

1 Project kick-off meeting to discuss overall project expectations, timelines, and deliverables.

Agreed protocols of the in vivo analgesic effect assays (with noted modifications, if necessary)

Within 2 working days following receipt of protocol.

5 calendar days after phone conversation.

2 Results of the 20 compounds evaluated in the in vivo analgesic study in laboratory rodent animals.

The major findings of any study should provide immediately following the completion of any study on any test substance.

180 calendar days from completion of Task 1.

3 Final Study Report 7 calendar days from completion of test substance in Task 2.

All Tasks Monthly Status Reports 30 days from contract award date and monthly thereafter.

VI. 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.

DEA Representatives (Scientific and Technical Contact):

Teneille D. Walker, Ph.D.

Pharmacologist Drug and Chemical Evaluation Section Drug Enforcement Administration Phone: 202-598-8894 Email: Teneille.D.Walker@usdoj.gov

Luli R. Akinfiresoye, Ph.D.

Pharmacologist Drug and Chemical Evaluation Section Drug Enforcement Administration Phone: 202-353-1461 Email: Luli.R.Akinfiresoye@usdoj.gov