Attachment2_SOW_updated 03221.docx

DOCX document 32 KB Posted Mar 3, 2021

Attached to: In Vitro Metabolism and Non-Clinical ADME Studies
Solicitation number: N01DA-21-8957
Issued by: Department of Health and Human Services National Institutes of Health National Institute on Drug Abuse

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Amendment 01_Solicitation N01DA-21-8957.docx	DOCX document	Mar 3, 2021

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Statement of Work updated on 03/02/21

BACKGROUND STATEMENT

A major mission of the National Institute on Drug Abuse (NIDA) is the development of safe and effective medications for the treatment of drug addiction. In 1989, Congress mandated the establishment of the Pharmacotherapies Development Program within NIDA. As a result of this mandate, in 1990 NIDA created the Medications Development Division, now the Division of Therapeutics and Medical Consequences (DTMC), to operationalize the goals of the program. The program supports every aspect of the medications development efforts including syntheses, bioanalytical chemistry, pharmacology, toxicology, pharmacokinetics/metabolism, and clinical evaluations of potential treatment medications through grants and contracts. The objectives of this contract are to provide in vitro metabolism and permeability services to the medications development program of the National Institute on Drug Abuse (NIDA).

The body generally eliminates drugs either by excretion of intact molecules or by biotransformation (metabolism) to more readily eliminated forms (metabolites). Because these metabolites may contribute to therapeutic efficacy or toxicity, it is important in the early stages of drug development to understand these metabolic processes. Of particular interest are the identification of the enzymes involved in metabolic pathways; individual variations in metabolic rates; and genetic polymorphisms in these enzymes that may alter their metabolic activity. All of these factors can significantly affect the safety and efficacy of drug candidates. One can characterize drug metabolism using simple, rapid, and low-cost in vitro methods to provide predictions of toxicity and efficacy which may significantly affect the design of preclinical in vivo studies and clinical evaluations.

In vitro metabolism studies use liver fractions (e.g., hepatocytes, microsomes) and tissue slices from different species (e.g., human, mouse, dog, monkey) to investigate interspecies variations in biotransformations. This data is useful in determining relevant animal models for preclinical evaluations of drug candidates. Further, in vitro studies allow for the determination of metabolic pathways and the identification and characterization of major metabolites to aid in the prediction of drug-drug interactions and potential sources of drug toxicity.

Another important concern in drug development is a compound’s ability to pass through biological membranes to reach the systemic circulation and therapeutic targets. Orally dosed drugs need to be absorbed by the gastrointestinal tract and pass through the intestinal wall to achieve sufficient bioavailability for therapeutic efficacy at target organs. Drugs intended to treat disorders of the central nervous system need to permeate the blood-brain barrier. In vitro permeability studies using relevant cell lines allow for the evaluation of a drug candidate’s ability to pass through biological membranes and to identify any transporters involved in its absorption across or efflux from the interior of these barriers.

Drug candidates that exhibit desirable in vitro properties need to be further evaluated in non-clinical in vivo animal models to determine absorption, distribution, metabolism, and elimination (ADME) properties, as well as to evaluate potential toxicity. These models are necessary to assess the compound’s bioavailability, the concentration of compound and/or metabolites versus time in the systemic circulation, the distribution of compound and/or metabolites into tissues, and its mode of elimination. These parameters are critical data on the pathway to first-in-human clinical trials.

NIDA is soliciting proposals from qualified businesses to provide in vitro metabolism and non-clinical ADME studies for its medications development program. The in vitro metabolism studies for this contract typically include metabolite profiling for interspecies comparison using liver fractions (Phase I and Phase II metabolism), enzyme phenotyping reactions, and enzyme inhibition and/or induction studies. Additional in vitro studies include determination of intestinal and blood-brain barrier permeability of new compounds. The non-clinical ADME studies typically include bioavailability, pharmaco/toxicokinetics, tissue distribution, and elimination studies. This contract will also include structure identification of major metabolites by mass spectrometry or nuclear magnetic resonance (NMR).

The objective of this contract is to carry out in vitro metabolism and permeability and in vivo ADME studies to support the medications development program of the National Institute on Drug Abuse (NIDA). NIDA and NIDA sponsored investigators will use the data obtained for submissions to the Food and Drug Administration (FDA) in support of Investigational New Drugs (INDs) and New Drug Applications (NDAs).

STATEMENT OF WORK

Task 1. Metabolic Stability

• Perform in vitro metabolism studies of submitted compounds by hepatic cells or subcellular fractions from a variety of species for estimation of metabolic stability and intrinsic clearance

Task 2.	Metabolic Pathway Identification (Reaction Phenotyping)
•	Perform in vitro metabolism studies to identify the enzymes (CYP450s and/or others) involved in the metabolism of submitted compounds
Task 3.	Enzyme Inhibition
•	Perform studies to evaluate submitted compounds for their potential to inhibit human hepatic CYP450 and/or other metabolic enzymes
•	Perform studies to determine if there are interactions between submitted compounds with drugs commonly abused by the target population, such as methamphetamine. These studies involve determination of Ki (inhibitory constant) and IC50 (the concentration required to inhibit enzyme activity by 50%) values for submitted compounds.
Task 4.	Enzyme Induction
•	Perform studies to evaluate submitted compounds for their potential to induce human CYP 450 enzymes and/or other metabolic enzymes
Task 5.	Metabolite Identification
•	Identify the structure of major metabolite(s) produced either by in vitro studies or in vivo systems (from biological samples obtained in other NIDA sponsored studies) by mass spectrometry and/or nuclear magnetic resonance (NMR). For proposal purposes, NIDA may not be able to provide reference standards of metabolites.
Task 6.	In Vitro Permeability Studies
•	Determine the intestinal permeability of new compounds in order to assess oral absorption using Caco-2 cells or other appropriate systems
•	Use appropriate cell-line to assess blood-brain barrier permeability of new compounds
•	Evaluate the permeabilities in the presence and absence of specific inhibitors of drug transport systems
o	Drug transport systems may include, but are not limited to, P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, and OAT3.
•	Determine the solubility of submitted compounds if such information is not available
Task 7.	Assay Development and Validation
•	Develop and validate sensitive assay methods (ng/mL or pg/mL) to quantify the study compound and its metabolite(s), as indicated, in biological matrices (e.g., plasma, urine) using LC-MS/MS or GC-MS/MS.
•	Assay methods must be validated for precision, accuracy, selectivity, recovery, sensitivity, stability (short and/or long-term), and effect of hemolysis according to the FDA guidance.
•	Provide services for handling of radioactive samples, when required.

Task 8. Bioavailability/PK Studies

•	Conduct bioavailability/PK studies in animal species (e.g., mice, rats, dogs, monkeys) according to the following guidelines
o	Three male and three female animals should be used in each dose group
o	Generally, up to three dose groups will be studied using IV, PO, or other designated routes of administration and designated dose levels
o	Plasma and/or urine will be collected and quantified for study compound and metabolite(s), as indicated, using methods developed for the study or as described in Task 7.
o	Relevant PK parameters, such as half-life, AUC, volume of distribution, relative bioavailability, or dose proportionality may be calculated, as appropriate
•	Conduct other PK studies (e.g., interaction studies and sub-chronic studies) as designated by the COR, in animal species (e.g., rats, dogs, monkeys) according to the following guidelines
o	Three male and three female animals should be used in each dose group
o	Biological samples (e.g., plasma, urine, feces) are to be collected and quantified for study drug and its metabolite(s), as indicated
o	Relevant PK parameters, such as half-life, AUC, volume of distribution, relative bioavailability, or dose proportionality may be calculated, as appropriate
o	Perform PK simulations to optimize PK blood sampling times or simulate steady-state PK based on single dose PK data to be conducted, as required

Task 9. Absorption, Distribution, Metabolism, and Excretion Studies

•	Conduct PK studies using radiolabeled study compound via IV or other designated route of administration to evaluate its absorption, distribution, metabolism and excretion according to the following guidelines
o	Equal numbers of male and female animals will be used in each dose group
o	In studies that do not include tissue distribution, at least three males and three females will be included in each dose group at each time point
o	Collection of samples generally will be for up to 168 hours post-dose
o	When metabolite profiling is to be performed in rodents, additional animals may be dosed for plasma collection at four time points
o	Tissue distribution samples may be analyzed by either quantitative whole-body autoradiography or excision/combustion techniques
o	Dosimetry calculations using tissue distribution results will be performed and a dosimetry report generated
o	Blood, plasma, urine, and feces are to be collected and assayed for total radioactivity
o	Unchanged study compound and metabolite(s) in plasma and urine, as indicated, will be assayed using methods described in Tasks 7 and 11
o	Plasma, urine, and feces will be profiled for the study compound and metabolite(s) using appropriate methods (e.g., LC with in-line radioactivity detection and mass spectrometry) and major metabolite(s) identified
o	Relevant PK parameters in blood, plasma, urine, feces, and tissues, such as half-life, AUC, plasma clearance of unchanged study compound, and excretion rates, shall be determined

Task 10. Toxicokinetic Analysis

•	Perform toxicokinetic analysis of the data generated under NIDA toxicology program
o	Estimation of toxicokinetic parameters and preparation of detailed reports
o	Reports shall be suitable for submission to the FDA as part of IND or NDA submissions

Task 11. Quantification of Study Compounds and Metabolites

•	Perform quantitative assays (using a validated assay method as described under Task 7) of a study compound and its metabolite(s) in biological samples submitted by other investigators authorized by the COR.
o	Most submissions will be blood, plasma, or urine samples from toxicology studies in mice, rats, dogs, monkeys, or humans

Task 12. Protein Binding Studies

•	Determine the percent of study compound bound to plasma protein by performing plasma protein binding studies such as equilibrium dialysis or ultrafiltration with LC-MS/MS detection
•	Samples may be from an in vivo bioavailability study
•	Radioactive study compounds with scintillation counting may be used in the assay
•	Plasma from different species (mouse, rat, dog, monkey, and human) shall be used to evaluate protein binding across species
•	Three different concentrations of the study compound will be used, depending on the sensitivity of the assay method

Task 13. Archival Maintenance of Records

• At the end of the contract period (when all analytical work is completed), all data, including laboratory notebooks, hard copies of raw data, and databases of assay results on disk or tape shall be placed in secure storage for a period of up to 5 years in case a GLP audit is required by FDA in connection with an IND or NDA submission. During this period, the contractor will be responsible for the integrity and organization of the material and its confidentiality. At the end of this period (or the Option below, if exercised), all reference material, data files, etc. will be disposed of per instructions of the COR.

Task 14. Administrative Support

•	Perform additional support services related to contract administration. The support services may include, but are not limited to, preparing deliverables as required by the contract (e.g., monthly/annual progress reports), meeting contract requirements, invoicing, monthly/annual progress reports, preparing monthly invoices, and general contract meetings. A list of possible example deliverables follows:
o	Annual Progress Reports;
o	Final Contract Report w/ Summary of Salient Results;
o	All data, etc. as directed by the COR;
o	Annual Utilization Reports;
o	Final Invention Statement (if applicable);
o	Reporting of Financial Conflict of Interest (FCOI);
o	Small Business Subcontracting Reports (if applicable);
o	Roster of Employees Requiring Suitability Investigations;
o	IT Security Plan;
o	IT Risk Assessment (if applicable);
o	FIPS 199 Assessment (if applicable);
o	IT Security Certification and Accreditation (if applicable);
o	Reports of New and Departing Employees; and
o	Non-Disclosure Agreements.

File details come from the government source that posted it. Updated Mar 3, 2021.