WO2001057760A1 - Systeme de traitement de donnees pour programmes de developpement de composes - Google Patents

Systeme de traitement de donnees pour programmes de developpement de composes Download PDF

Info

Publication number
WO2001057760A1
WO2001057760A1 PCT/US2001/003011 US0103011W WO0157760A1 WO 2001057760 A1 WO2001057760 A1 WO 2001057760A1 US 0103011 W US0103011 W US 0103011W WO 0157760 A1 WO0157760 A1 WO 0157760A1
Authority
WO
WIPO (PCT)
Prior art keywords
development
user
studies
data
software
Prior art date
Application number
PCT/US2001/003011
Other languages
English (en)
Inventor
Bradley B. Brown
Michael Campbell
Michael Drewery
Gail F. Mcintyre
Kenneth Rehder
Original Assignee
Ppd Discovery, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ppd Discovery, Inc. filed Critical Ppd Discovery, Inc.
Priority to AU34657/01A priority Critical patent/AU3465701A/en
Priority to CA002398892A priority patent/CA2398892A1/fr
Priority to EP01906790A priority patent/EP1261929A1/fr
Publication of WO2001057760A1 publication Critical patent/WO2001057760A1/fr

Links

Classifications

    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06Q—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES, NOT OTHERWISE PROVIDED FOR
    • G06Q10/00—Administration; Management
    • G06Q10/06—Resources, workflows, human or project management; Enterprise or organisation planning; Enterprise or organisation modelling
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/90—Programming languages; Computing architectures; Database systems; Data warehousing
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/30—Prediction of properties of chemical compounds, compositions or mixtures
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/40—Searching chemical structures or physicochemical data

Definitions

  • the present invention relates to a data processing system forproviding a development program for a bioactive compound.
  • the data processing system calculates the cost, time and quantity of material associated with a certain development program as it relates to a certain bioactive compound based on information and selections entered by the user.
  • the system also determines potential conflicts that would impede a development program.
  • the system also detemiines safety margins for a development program.
  • One way to increase the success rate is to prioritize bioactive compounds best suited for development earlier in the process by comparing different candidates based on their likelihood of success in a development program.
  • PK pharmacokinetics
  • compounds can be toxic to an animal, can have undesirable pharmacokinetics (PK) profiles such as a short half-life or extensive metabolism, can be genotoxic, and can have non-predictive toxicities that are outside of the pharmacological effects .
  • PK pharmacokinetics
  • the data processing system of the present invention provides a bioactive compound developer with an interactive tool that allows the developer to create customized development programs that address general reasons for development failure as well as specific issues related to a particular compound such as mechanism of action, the indication being treated and predicted toxicities based on chemical structure. Based on information provided by developer, the system analyzes such information relative to studies typically required for development and provides, for example, time, cost, quantity of material, conflict and safety margin information.
  • a data processing system and method according to the present invention provides a developer the opportunity to assess different development programs that could be used to develop a bioactive compound as a candidate for regulatory agency approval based on the numerous parameters that affect such assessment. By determining a development program using the present invention, the potential risks and benefits of the development program can be assessed cheaply and quickly.
  • the present invention includes a data processing system and method for providing a development program for a bioactive compound.
  • the system is interactive such that the analysis performed by the system is based on information selected or entered by a user.
  • the development program can be designed by a user prior to entry into the system or created by user from within the system, h particular, the data processing system provides software for prompting a user to input certain specified development data, including for example information regarding chemical properties, intended use, pharmacology, toxicology, safety pharmacology, and technical and patent publications.
  • the system determines time, cost and quantity of materials of a particular development program based on such information provided by user.
  • the system also identifies potential conflicts and assesses the safety margins of the development program.
  • One embodiment of the present invention is a system for providing a development program for a bioactive compound comprising: a computer processor for executing computer software; a first computer storage medium coupled to said computer processor for storing computer software and data; software for prompting a user to input development data; software for processing said user input development data; and software for displaying said processed development data to generate a development program output.
  • a particularly preferred first computer storage medium stores data regarding information needed to design a development program for submission to a regulatory agency.
  • the present invention also includes a system for providing a development program for a bioactive compound for submission to a regulatory agency, which includes a computer processor for executing computer software and a first computer storage medium coupled to said computer processor for storing computer software and data.
  • the first computer storage medium comprises a database comprising one or more tables selected from the group consisting of a materials quantity table, a conflicts table, a financial table and a temporal table.
  • the system also includes software for prompting a user to input development data for a purpose selected from the group consisting of evaluating the chemistry of said bioactive compound, optimizing the chemical properties of said bioactive compound, defining the intended clinical program, evaluating primary pharmacology, evaluating ADME, selecting safety pharmacology studies, evaluating toxicology, literature evaluation and patent evaluation.
  • the system also includes software for processing the user input development data and software for generating a development program output based on the input development data.- The output includes an output selected from the group consisting of time, cost, quantity of materials, and conflicts.
  • the software for prompting, processing and generating is iterative.
  • the present invention also includes a computer-implemented method for providing a development program for a bioactive compound.
  • This method includes prompting a user to input development data, processing the user input development data, and generating a development program output based on said input development data.
  • Fig. 1 depicts a flowchart of flow of information through the data processing system according to the present invention.
  • Fig. 2 illustrates the display of educational text by the data processing system according to the present invention.
  • Fig. 3 depicts a software routine for a main menu used in the data processing system according to the present invention.
  • Fig. 4 is an example of a Chemistry Evaluation Form.
  • Fig. 5 is an example of a Lead Optimization Fonn.
  • Fig. 6 is an example of a Literature and Patent Evaluation Form.
  • Fig. 7 is an example of an Intended Clinical Program Form.
  • Fig. 8 is an example of an Absorption Form.
  • Fig. 9 is an example of a Distribution Form.
  • Fig. 10 is an example of a Metabolic Prediction Form.
  • Fig. 11 is an example of an In Vitro Metabolism Form.
  • Fig. 12 is an example of a Drag-Drug Interaction Form.
  • Fig. 13 is an example of an Excretion Form.
  • Fig. 14 is an example of a Safety Pharmacology Form.
  • Fig. 15 is an example of an Acute Toxicology Form.
  • Fig. 16 is an example of a Subacute Toxicology Form.
  • Fig. 17 is an example of a Chronic Toxicology Form.
  • Fig. 18 is an example of a Carcinogenicity Toxicology Form.
  • Fig. 19 is an example of a Mutagenicity Form.
  • Fig. 20 is an example of a Reproductive Toxicology Form.
  • Fig. 21 is an example of a Special Toxicity Form.
  • Fig. 22 depicts the software routine for the input and output of data using the data processing system according to the present invention.
  • Fig.23 illustrates a Gantt chart, request for safety margin determination and conflict text displayed by the data processing system according to the present invention.
  • Fig. 24 illustrates a Gantt chart described in the Example.
  • Fig. 25 illustrates an additional Gantt chart described in the Example.
  • Fig. 26 illustrates an additional Gantt chart described in the Example.
  • providing a development program refers to determining, identifying, defining, analyzing or proposing a development program.
  • a development program refers to the tasks that need to be performed to design, implement and complete studies that provide suitable information for obtaining approval of a product by a regulatory agency.
  • a development program can include a preclinical, Phase I, Phase II or Phase III studies, equivalents thereof for submission to regulatory agencies outside of the United States, or intermediate programs, e.g., Phase 11(a) or Phase ⁇ (b) studies.
  • a bioactive compound as referred to herein includes, but is not limited to, a compound that was produced by chemical synthesis, a compound that was isolated from its natural environment, a biological compound synthesized in vitro, or any other compound suitable for use as a therapeutic agent or agricultural product that requires marketing approval by a regulatory agency.
  • the data processing system of the present invention is used once a user of the system identifies one or more bioactive compounds of potential interest for further development.
  • a user is interested in providing a development program of a bioactive compound.
  • the user makes use of a personal computer.
  • the computer is programmed with software that is commonly used to access the Internet. Examples of software include Internet Explorer or Netscape Navigator with Java Enabled by way of Web Interface.
  • the computer is capable of being used to input data and print output data and/or store output data on any standard type of storage medium.
  • the user provides information and receives information from a development data processor using software applications described in detail herein. The user may enter or change data at any time during use of the system.
  • the user may also provide information and receive information from a development advisor, who is responsible for design or analysis decisions regarding a development program.
  • the information flow between user and development advisor as illustrated in Fig. 1 maybe accomplished in whole or in part by physical transfer of printed materials or over communication lines, such as accessing the same session on the system.
  • the system contains information regarding, for example, the steps needed to complete various development program options, the dependency between such steps to complete various development program options, the pre-requisites needed to complete various development program options, the time needed to complete various development program options, the cost of various development program options, the materials needed to complete various development program options, or potential conflicts during completion of various development program options.
  • steps to complete various development program options include, for example, determining dosing requirements, performing in vitro assays or testing in animal models.
  • Such entry point can include software that secures the session by prompting user to enter certain identification information such as user identification information (User ID), password information (Password), session identification information (Session ID), date infomiation (Date).
  • User uses the same identification information to re-enter the system and/or a particular session. If any portion of the identification information is not correct, the system will not proceed beyond the session entry point.
  • Once user has successfully entered the system user has a choice to proceed from session entry to multiple information sites through software modules that enable user to access a particular site.
  • Such information sites provide user with information needed to provide a development program containing information applicable to a submission to a regulatory agency.
  • the information accessed by user includes educational information, definitions of various terms applicable to development programs, different databases containing technical information such as compound structures, research articles and information about completed clinical studies and links to useful sites on the Internet.
  • Preferred infomiation sites of the present system include Definitions, Reference Databases and Useful Links. The system displays information contained at each information site.
  • a user may proceed from the starting point of the system to the Definitions site where user may select a particular educational text related to development programs from a definitions index.
  • the user proceeds from the starting point to the software module that prompts the user to select information to be reviewed by user.
  • Information is made visible to user as HTML text.
  • educational text includes information defining a variety of regulatory, pharmacokinetics, pharmacology, chemistry, toxicokinetic, toxicology, metabolism or drug development terms. Such information is based on, for example, know-how or information in published literature including, for example, text books, government documentation, research articles or clinical studies.
  • Example of terms to be defined include, but are not limited to oral absorption, acute toxicity, auto-induction, bioavailability, CAC, CaCO-2, cassette-dosing, chronic CTA, cytochromeP450, distribution, drag substance, drag drag interactions, ERC, excretion, excretion-balance, smdy, FDA, fertility index, gestation index, GLP ("Good Laboratory Practice"), hepatocytes, ICH, IND, induction, inhibition, lactation index, Log P, MTD, metabolites, microsomes, metagenesis, NDA, NOEL, pharmacophore, Phase I / Phase II, protein binding, QSAR, reproductive toxicity, Request for friactivation of IND, reversible toxicities, S AR, S9 subcellular fractions, safety margin, Segment I, Segment ⁇ , Segment III, sensitive species, subacute/subchronic toxicity, teratogenicity, toxicokinetics, toxicologically relevant species, transspecies carcinogen and/or viability index
  • the system can display appropriate text, such as text for an IND filing as shown in Table 1 :
  • IND Investigation New Drag Application. An IND is required to exempt Sponsors from registering a product in order to transport drug across state lines and conduct investigational clinical studies. Certain preclinical studies are required to demonstrate the product is unlikely to cause harm to subjects/patients.
  • a user may proceed from the starting point to the Reference Databases site where user may access one or more databases that include, for example, a structural database containing information about chemical structures, a clinical database containing information about prior clinical studies, or a literature database containing information about scientific articles or patent publications. Other databases may be added to the system as needed.
  • the user may also access different Internet sites that provide similar types of information, such as NEH's PubMed site, the United States Patent and Trademark Office patent search site or regulatory agency sites. Such Internet sites may be accessed through the Useful Links site.
  • Examples of Internet sites include MedLine, Toxline, uspto.gov, fda.gov, usda.gov, epa.gov, patent.womplex.ibm.com, www.eudra.org/emea.html, www.ifpma.org, www.ilsi.org.hesiprotocols, sis.nlm.nih.gov or http://ntp-server.niehs.nih.gov.
  • a skilled artisan will recognize that different websites may be deleted or added as needed.
  • development data input by user at the data entry site flows through modules of software with the starting point being session entry. A user may proceed from the starting point to the software module that prompts the user to input development data. At this module, user may input new data or modify existing data from the same session or a prior session. The system can store the entered data for later access. Following entry of development data, the user executes the data entry and sends the entered information to the development data processor.
  • data is automatically passed to the following value calculations modules: time allocation; cost allocation and required quantity of materials.
  • the software will proceed to calculate the time, cost and materials quantity value from data entered by user.
  • Such data is referred to herein as processed user input development data and also includes conflict or safety margin information described herein.
  • the system then produces output and stores the processed data.
  • the output data is referred to herein as development program output and also includes conflict or safety margin output described herein.
  • the system asks the user to enter certain development data for the purpose of, for example, evaluating the chemistry of the bioactive compound of interest, optimizing the chemical properties of the bioactive compound, defining the intended clinical program for the compound, evaluating the primary pharmacology of the compound, evaluating the absorption, distribution, metabolism and excretion (ADME) characteristics of the compound, selecting safety pharmacology studies, evaluating toxicology and/or evaluating information in the published scientific or patent literature.
  • the system may prompt the user to input development data regarding the chemistry of the bioactive compound including, for example, the physical properties, structural confirmation, method of synthesis, compound availability or isotopic stably labeled compound availability of the bioactive compound.
  • the system may also prompt the user to input development data regarding studies to evaluate the primary pharmacology of the compound.
  • the system may also prompt the user to input development data regarding lead optimization of the bioactive compound, including for example, defining the absorption, metabolism, toxicity or distribution studies to be performed.
  • the system may also prompt the user to input development data regarding published literature known to user, including for example, identifying previous clinical studies, patent publications, literature publications or computational information.
  • the system may also prompt the user to input development data regarding the clinical program user intends to use, including for example, the class of the bioactive compound, the indication to be treated, the anticipated dose, the duration of treatment or the study population.
  • the system may also prompt the user to input development data regarding studies to determine the ADME characteristics of the bioactive compound, including for example, defining absorption studies, distribution studies, metabolism studies or excretion studies.
  • the system may also prompt the user to select particular safety pharmacology studies to be performed.
  • the system may also prompt the user to input development data regarding studies to evaluate the toxicology of the bioactive compound of interest, including for example, defining acute toxicity studies, single-dose toxicity studies, repeat dose toxicity studies, carcinogenicity studies, gentoxicity studies, reproductive toxicology studies or special toxicity studies.
  • the system prompts the user to input development data shown in Figs. 4 through 21.
  • Fig. 3 is a flowchart depicting the route of information to be used by the data processing system according to the preferred embodiment of the present invention.
  • the system starts at session entry by user and proceeds to a main menu.
  • the system provides access to the main menu from other parts of the system, represented by a "H" in Fig. 3.
  • the main menu lists the various sites of the system that can be accessed by user.
  • a main menu contains major headings including: Introduction; Chemistry; Lead Optimization Program; Supporting the Clinical Program; Lead Profile/Preclinical Program; Primary Pharmacology; ADME/PK; Safety Pharmacology; Toxicology; Definitions; Search First PassTM; Reference Databases; Form Links; Useful Links; and Home.
  • the system next proceeds to the appropriate site when the user enters a menu choice.
  • the system determines that Definitions was selected by user, it asks user to select a particular definition by displaying a definition index containing choices of terms. User selects a term and the system displays text comprising a definition of the selected term. If the system determines that Useful Links was selected by user, it asks the user to select a particular Internet link and then provides a hyperlink to the selected Internet site. If the system determines that Reference Databases was selected by user, it asks the user to select a particular database and then the system will enable user to search the selected database using a standard search tool, such as a boolean search tool. If the system determines that Form Links was selected by user, it then asks the user to select a particular development form and then proceeds to the development form selected by user.
  • a standard search tool such as a boolean search tool.
  • the system determines that either Chemistry, Lead Optimization Program, Supporting the Clinical Program, Lead Profile/Preclinical Program, ADME/PK, Safety Pharmacology or Toxicology site was selected by user, it then proceeds to a page that contains instructional text about the particular site chosen by user.
  • Each instractional text page prompts user to select the development form related to that topic. As such, more than one form may be accessed from an instructional text page because the topics are related.
  • the system asks the user to select or enter certain data and the user proceeds with data entry. The system displays the entries on the development form and then prompts the user to submit the data. The data entries are not stored by the system until user submits the data. User may return to a form for which data has already been submitted to modify the data.
  • a system of the present invention displays instractional chemistry text that explains the type of chemical information user will need to provide a development program and the importance of such information.
  • Instractional chemistry text may also include information regarding, for example, physical properties, structural confirmation, method of synthesis, compound availability or stable isotopic or radioisotopic labeled compound availability.
  • a system of the present invention displays instractional lead optimization text that explains the importance of optimizing a compound that is a development candidate and describes various criteria of an optimization program such as performing a literature and computational evaluation of the development candidate to, for example, compare physicochemical and biological properties, e.g., mechanism of action or therapeutic indication, to known drags with analogous properties, predict the physicochemical and biological properties e.g., absorption or metabolism, by extrapolation of these properties from known drugs, or develop a quantitative structure-activity relationship or identification of key pharmacophoric regions.
  • physicochemical and biological properties e.g., mechanism of action or therapeutic indication
  • known drags with analogous properties predict the physicochemical and biological properties e.g., absorption or metabolism, by extrapolation of these properties from known drugs, or develop a quantitative structure-activity relationship or identification of key pharmacophoric regions.
  • a system of the present invention displays instructional preclinical design program text that explains certain tasks that can make a preclinical development program more efficient including, but not limited to, submission of unaudited toxicology data with original submission and commitment to finalize reports within 120 days of first dose in the clinic, performing screening INDs or preparing and submitting pre-IND packages and arranging pre-IND meetings with the FDA.
  • a system of the present invention displays instructional preclinical design program text that explains certain tasks that can make a preclinical development program more efficient including, but not limited to, submission of unaudited toxicology data with original submission and commitment to finalize reports within 120 days of first dose in the clinic, performing screening INDs or preparing and submitting pre-IND packages and arranging pre-IND meetings with the FDA.
  • a system of the present invention displays instructional preclinical design program text that explains certain tasks that can make a preclinical development program more efficient including, but not limited to, submission of unaudited toxicology data with original submission and commitment to finalize reports within 120 days of first dose in
  • instractional ADME/PK text may also contain text that explains factors that can affect absorption and different types of absorption assays that can be performed including, for example, single dose pharmacokinetics or repeat-dose pharmacokinetics.
  • instractional ADME/PK text may also contain text that explains the significance of performing distribution studies and the types of studies that can be performed including, but not limited to, single dose tissue distribution studies, repeated dose distribution studies or in vitro distribution studies.
  • instructional ADME/PK text may also contain text that explains the importance of performing metabolism studies, describes Phase I IND requirements, describe different drags that induce, inhibit or are substrates for specific cytochrome P450 isozymes or describes metabolic assays suitable for development of compounds that identify the cytochrome P450 enzymes responsible for transforming a development candidate into one or more active or inactive metabolites, identify potential drag-drag interactions, compare species-specific routes of elimination, or facilitate the lead optimization process.
  • metabolic studies suitable for a development program include, for example, intact liver system studies, liver microsome/S9 subcellular fraction assays, recombinant cytochrome P450 in vitro assays, enzyme induction assays, co- incubation of two study compounds with microsomes, S9 fractions, or recombinant cytochrome P450 isozymes or single- and repeat-dose pharmacokinetic studies.
  • instractional ADME/PK text may also contain text that explains that a variety of mechanisms by which drags are excreted by the body and information important to analyzing the occurrence of excretion including, for example, mass balance studies that can be conducted prior to initiating clinical studies to provide information regarding the extent of clearance in the urine, feces and/or bile, and expired air and the time taken to clear the majority of a dose.
  • a system of the present invention displays instructional safety pharmacology text that explains the importance of performing safety pharmacology studies and describes studies that investigate the effect of a compound on different systems in the body including, for example, in vitro receptor binding screens that assess the compound's abilityto competitively inhibit compounds that bind to various receptors, ex vivo, in vivo or in vitro models in systems such as neuropharmacological, cardiovascular/respiratory, gastrointestinal, genitourinary, endocrine, anti-inflammatory, immunoactive, chemotherapeutic, enzyme effects or behavioral activity, or drug interaction studies such as studies using pentobarbitone- and or zoxazolamine or in vitro tests using cytochrome P450 isozymes.
  • a system of the present invention displays instractional toxicology text that explains the purpose and importance of performing toxicology studies, provides information regarding different types of toxicology studies including their duration, when they are performed during a development program, the results observed from such smdies and special circumstances that might arise during a development program that require particular toxicology steps.
  • Instractional toxicology text can also include information regarding different types of toxicology studies needed for a Phase I IND including, for example, acute /expanded acute smdies, subchronic/subacute (typically ⁇ 90 days) smdies or genotoxicity studies.
  • the instractional toxicity text can indicate that there are specific toxicology studies that may be conducted when the compound being developed is an oligonucleotide, an oncology product or a biological product.
  • Instructional toxicology text regarding oncology products can explain methods to confirm how reduction in tumor load relates with the mechanism of action of a cytotoxic agent, cell culture assays to assess cytotoxicity or cytostatic ability against various tumor cell lines, nude mouse Human xenograft models, metastasis nude mouse models or cytotoxicity studies with non-cancer cells.
  • Instractional toxicology text regarding biological products can describe the types of animal models that can be used with biological products and the toxicology studies that are or are not applicable to biological products including, for example, chronic smdies, genotoxicity studies, reproductive toxicology smdies or carcinogenicity smdies.
  • a system of the present invention displays instractional subacute toxicology text that explains when subacute toxicity studies are useful and the type of information that can be derived from such studies.
  • "subacute” and “subchronic toxicity” are interchangeable terms referring to an experiment in which a drag is administered for a limited period usually 2-4 weeks up to 90 days.
  • a system of the present invention displays instractional chronic toxicology text that explains the design and factors affecting the duration of chronic toxicity studies.
  • toxicity studies of a duration longer than 90 days are referred to as "chronic.”
  • a system of the present invention displays instractional carcinogenicity smdies for toxicology text that explains when carcinogenicity smdies need to be performed and different types of studies including, but not limited to, carcinogenicity studies for topicals, bridging carcinogenicity studies or transgenic models.
  • Instructional carcinogenicity studies for toxicology text may also contain information regarding submissions of carcinogenicity study design to the Carcinogenicity Assessment Committee (CAC) of the FDA.
  • CAC Carcinogenicity Assessment Committee
  • a system of the present invention displays instractional genotoxicity text that explains genetic toxicology and its relationship to carcinogens that are mutagens and assays that can be used to test for mutagenic activity including, for example, Ames tests, in vitro tests for chromosomal damage or in vivo tests for chromosomal damage.
  • instractional genotoxicity text can contain information regarding chemical structures related to the carcinogenic and/or mutagenic potential of chemicals.
  • a system of the present invention displays instructional reproductive toxicology text that explains the need to test for a chemical's adverse effects on the male or female reproductive system and the types of smdies that can be used to test for reproductive toxicity including, for example, fertility and general reproductive performance smdies, teratogenicity studies, perinatal and postnatal smdies that determine the effects of a compound on the suckling and lactating dam and the development of the newborn or multigenerational smdies that investigate the effects of the drag throughout a number of generations.
  • the instructional reproductive toxicology text can also contain information regarding the timing of such studies and interpretation of results obtained from such studies.
  • a system of the present invention displays instractional special toxicity text that explains when special toxicity smdies need to be performed and the types of smdies that are useful in a development program, such as dermal irritation smdies to test topical products, dermal sensitization studies for products that will come in contact repeatedly with the skin, ophthalmic irritation studies for opthamological products, ototoxicity studies for otic preparations or vascular irritation smdies for intravenous formulations.
  • the data Upon submission of data in a development form, the data automatically passes to the value calculation software module and the system displays the time, cost and materials quantity data calculated by the system from the data entered by user.
  • Such calculations can be displayed in any appropriate numeric and/or graphic form.
  • the time data typically displays the total amount of time required for all the activities in the preclinical development program.
  • the time data displays the amount of time for individual activities, as well as the relative order or overlap of individual activities.
  • such calculations are displayed as a Gantt chart as illustrated in Fig.23.
  • the system re-calculates and modifies the display of the calculations each time user modifies the data in such a manner that results in a change in the calculations.
  • the system retrieves the data, calculations and display from a session if user re-enters the session at a later time using the same Session ID.
  • the system determines that user has selected primary pharmacology from the main menu, it then proceeds to the primary pharmacology site at which user may select to view information on a variety of topics related to primary pharmacology.
  • topics related to primary pharmacology include antiinfectives, AIDS/HIV, hepatitis, analgesics, Alzheimers, vaccines, antirheumatic disease therapy, obesity, immunomodulators, oligonucleotides, oncology, osteoarthritis, osteoporosis and topical microbicides.
  • the system proceeds to a site containing information about the topic and displays such information.
  • primary pharmacology information contains information regarding background information about primary pharmacology, and when and why primary pharmacology studies are performed.
  • a system of the present invention displays text about antirheumatic disease therapy that describes the types of smdies that can be performed when developing an antirheumatic disease therapy including, for example, pharmacokinetic smdies, in vitro systems useful for defining the potential mechanism of action of a compound, in vivo models useful for determining pharmacodynamic responses, similarity of animal disease etiology to clinical disease or mechanism-based toxicity, toxicology smdies including reproductive toxicity studies, or studies useful for selecting compounds that inhibit cells and processes responsible for rheumatoid arthritis.
  • a system of the present invention displays text about antiinfectives that contains information related to particular organisms and the diseases they cause.
  • a system of the present invention displays text about HIV regarding the disease it causes and tests that are suitable for the development of an anti-HIV therapeutic product including, for example, testing a compound for effect in primary cells infected with the virus to obtain a therapeutic index, testing a compound for effect against low passage clinical virus isolates that come from diverse areas of the world and determine IC50 and IC90 values, determining dose-response relationship against the virus, determining the effects on multiplicity of infection, determining the effects timing of treatment has on antiviral activity, determining the rate of resistance, or testing the compound in an appropriate retrovirus- infected animal.
  • a system of the present invention displays text about analgesics that explains animal models of hyperalgesia, such as the formalin lick test, the abdominal constriction test, the adjuvant-induced arthritis test, or the tail flick to radiant heat test.
  • a system of the present invention displays text about Alzheimers Disease including information about tests typically conducted for Alzheimer's products. Such tests include, for example, passive avoidance tests, eight-arm radial maze tests, or Morris Water Maze tests.
  • a system of the present invention displays text about oncology that explains the need for and describes suitable smdies for developing an anti-cancer product, such smdies including, for example, cell culture assays to assess cytotoxicity, nude mouse human xenograft models, nude mouse models to assess potential for a compound to inhibit metastasis, cytotoxicity smdies with non-cancer cells, twenty-eight-day toxicity smdies, genotoxicity smdies, toxicology smdies of longer duration if clinical studies of greater than 28 days are required for the development program, carcinogenicity studies, or combination toxicity smdies.
  • a system of the present invention displays text about osteoporosis that explains the need to perform smdies that demonstrate that long term treatment will not lead to deleterious effects on bone quality.
  • the osteoporosis text can also contain information describing how to design an osteoprosis development program including descriptions of suitable animal models and parameters that can be monitored during such animal smdies.
  • a system of the present invention displays text about obesity that provides examples of animal models used to test anti-obesity compounds, such as obese rodent animal models, and explains safety and toxicology issues associated with different patient populations that can be used in a development program for an obesity product.
  • a system of the present invention displays text about immunomodulators that explains the need to provide evidence of immunomodulatory activity of an anti-HIV compound prior to initiating clinical smdies including, for example, characterizing the mechanism of action, safety profiling, antiviral activity is distinct from any cytotoxicity or information regarding how immunomodulators work.
  • a system of the present invention displays text about oligonucleotides that explains toxicology issues associated with antisense compounds including, for example, adverse effects such as sequence-dependent and sequence independent effects or cardiovascular toxicity.
  • the oligonucleotide text can also include information that describes studies suitable for Phase I IND submissions, starting doses in clinical smdies or bone marrow purging.
  • a system of the present invention displays text about osteoarthritis that explains the symptoms that characterize osteoarthritis such as pain, biochemical and enzymatic changes, cartilage fragmentation and loss, osteophyte formation and bony sclerosis, as well as smdies suitable for the development of an osteoarthritis therapeutic including, for example, animal models, osteoarthritis measurements in clinical trials, pain global assessments, pain and function measurements or structural measurements.
  • a system of the present invention displays text about topical microbicides for prevention of HIV and other sexually transmitted diseases that provides background information regarding such therapeutics and describes suitable assays useful in the development of such topical microbicide products including, for example, activity assays, mechanism of action assays, in vivo smdies, formulation testing, or toxicology requirements.
  • the system determines whether a conflict exists in the data selected by user. Data from the two or more forms is automatically passed to the conflict catcher software module. The software will proceed to identify the conflict and then the system then produces output.
  • the system displays text describing the conflict identified by the system. Such text is preferably displayed in conjunction with the time, cost, materials quantity output, such as shown in Fig. 23.
  • the system may detect a conflict if: the intended duration of a clinical study entered by user in an Intended Clinical Program Form exceeds that of the longest duration of the Subacute Toxicity Form if no chronic toxicity smdies are indicated on the Chronic Toxicity Form; the intended clinical smdy entered by user on an Intended Clinical Program Form includes either pediatric or elderly subjects but the toxicology studies entered by user on a Sub-Acute and/or Chronic Toxicity Form do not plan to test the drag in juvenile or elderly animals, respectively; or the intended clinical study entered by user on an Intended Clinical Program Form will enroll female or male subjects only but the toxicology smdies entered by user on a Sub-Acute and/or Chronic Toxicity Form do not plan to test the drug in the appropriate sex or at least in both sexes. If any of these or other such conflicts are identified by the system, the system displays explanatory text and associated tabular information which can include clickable links to other relevant sections of the program, such as the following shown in Table 2:
  • the system has determined that the selections made for the toxicology smdies and the intended clinical program are in conflict.
  • the selections for elderly and pediatric populations from the Intended Clinical Program Form must match the elderly and juvenile animals selections from the toxicology forms.
  • the duration of the Intended Clinical Program Form must be the same or shorter than that of the toxicology smdies. Please make the necessary changes here. This will update the smdies concerned.
  • GMP Good Manufacturing Practice
  • non-GMP material and non-GLP preclinical studies as calculated from Acute Toxicology Form, Sub-Acute Toxicology Form, Chronic Toxicology Form, Drag-Drag Interaction Form, In Vitro Metabolism Studies Form, Carcinogenicity Smdies Form, Special Toxicology Smdies Form, Reproductive Toxicology Smdies Form, and/or Lead Optimization Form.
  • the system displays text that indicates to the user that there is a discrepancy.
  • Drag-Drug Interaction Form "Identification of up-regulated liver isozymes in livers of animals used in toxicological studies", but no repeat-dose toxicology study has been selected by user on a Sub-Acute Toxicology Form, then the system asks the user to modify the plan such that either a sub- acute study is selected or the repeat-dose pharmacokinetic information will come from an independent study, e.g., the in vitro hepatocyte assay.
  • oligonucleotide into the class of compound on an Intended Clinical Program Form and a monkey acute toxicity smdy assessing cardiovascular function has not been entered by user on an Acute Toxicity Form, then the system displays text indicating that the user has the option to select an acute monkey toxicity study with cardiovascular assessments.
  • a Toxicology instractional text page indicating that user is using the development program being provided by the system for a Phase I IND and no smdies are chosen from at least one form including an Acute Toxicity Form, a Sub- Acute Toxicity form, a Genotoxicity Form, an Absorption Form, a Distribution Form, an Excretion Form, an In Vitro Metabolism Form, or a Safety Pharmacology Form, then the system displays text asking if the user want to go back to any of these forms.
  • a Phase ⁇ IND and no smdies are chosen from at least one form including an Acute Toxicity Form, a Sub-Acute Toxicity form, a Genotoxicity Fonn, an Absorption Form, a Distribution Form, an Excretion Form, an In Vitro Metabolism Form, a Drag-Drag Interaction Form, a Reproductive Form or a Safety Pharmacology Form, then the system displays text asking if the user want to go back to any of these forms.
  • a Toxicology page indicating that user is using the development program being designed or evaluated by the system for a Phase III IND and no smdies are chosen from at least one form including an Acute Toxicity Form, a Sub- Acute Toxicity form, a Genotoxicity Form, an Absorption Form, a Distribution Form, an Excretion Fonn, an In Vitro Metabolism Form, a Drug-Drag Interaction Form, a Reproductive Form or a Safety Pharmacology Form or a Carcinogenicity Form, then the system displays text asking if the user want to go back to any of these forms.
  • a Toxicology page indicating that user is using the development program being designed or evaluated by the system for an NDA and no studies are chosen from at least one form including an Acute Toxicity Form, a Sub-Acute Toxicity form, a Genotoxicity Form, an Absorption Form, a Distribution Form, an Excretion Form, an In Vitro Metabolism Form, a Drag-Drug Interaction Form, a Reproductive Form or a Safety Pharmacology Form or a Carcinogenicity Form or a Chronic Toxicity Form, then the system displays text asking if the user want to go back to any of these fonns.
  • the conflicts described herein are intended to be examples of conflicts. One of skill in the art will recognize that additional conflicts may be added to the system based on technical requirements of smdies within a development program.
  • the system may query user to prompt the system to calculate safety margins. Preferably, such query is displayed on the Gantt chart when other output values of the system are displayed, as shown in Fig.23. If user selects calculation of safety margins, the system automatically proceeds to a safety margin site and uses the data entered by user to calculate the safety margins. In particular, the system calculates safety margin values after user has entered data into the system using either a subacute toxicology, acute toxicology or chronic toxicology development form, and an intended clinical program form. Following such calculations, reasonable and unreasonable safety margin values can be displayed in different colors, preferably the reasonable safety margin values are shown in the color green and unreasonable safety margin values are shown in the color red.
  • a system of the present invention displays safety margin information and calculations that educate the user regarding how safety margin values are determined relative to the type of development program smdies being performed.
  • An example of a safety margin output displayed by the system is shown in Table 3.
  • An example of how to convert an amount per body weight dose to body surface area is shown in Table 4.
  • a mg/kg dose to a body surface area dose, multiply the mg/kg dose by the conversion factor in kg/m 2 .
  • a 10 mg/kg dose is 10 x 37 or 370 mg/m 2 .
  • One embodiment of a system of the present invention comprises: a computer processor for executing computer software; a first computer storage medium coupled to the computer processor for storing computer software and data; software for prompting a user to input development data; software for processing said user input development data; and software for displaying said processed development data to generate a development program output.
  • a computer processor of the present invention includes any hardware that is suitable for executing software such as a computer server.
  • An example of a suitable server is a Compaq Proliant server.
  • the server is programmed with software suitable for managing input, output or information storage, such as Microsoft Windows® NT software.
  • One aspect of the first computer storage medium comprises a database that comprises one or more tables that contain data regarding the steps needed to complete various development program options; the dependency between such steps to complete various development program options; the pre-requisites needed to complete various development program options; the time needed to complete various development program options; the cost of various development program options; the materials needed to complete various development program options; potential conflicts during completion of various development program options; or the safety margins based on dose and toxicity.
  • steps to complete various development program options include, for example, determining dosing requirements, performing in vitro assays or testing in animal models.
  • the first storage medium stores the User ID, Password, Session ID and Date information entered by a user.
  • the first computer storage means comprises one or more tables including a temporal table, a financial table and a materials quantity table.
  • the temporal table comprises data regarding the time typically required to complete a certain task in a development program.
  • the temporal table contains information that the time needed for the duration of treatment during a subacute toxicology study is typically less than ninety days while a chronic toxicology study typically takes greater than ninety days to complete.
  • the financial table comprises data regarding the typical cost of completing a certain task in a development program.
  • the financial table provides a monetary value for a given task.
  • the materials quantity table comprises data regarding the amount of bioactive compound needed to complete a certain task in a development program.
  • the materials quantity table contains information that the amount of material typically needed for a single dose smdy is a certain gram amount while a long term study may require four times that amount.
  • data contained in the tables of the first computer storage means can be modified or updated over time.
  • the data contained in the temporal table is based on the complexity of the task being performed, the method being used to perform the task or any regulatory agency guidelines indicating the length of time needed to complete at least a portion of a particular task.
  • the data contained in the financial table is based on, for example, costs associated with the type and quantity of reagents, the length of the smdy, overhead, equipment and personnel needed to complete a task, among other parameters.
  • the data contained in the materials quantity table is based on the activity of the bioactive compound, or a derivative thereof such as a radiolabeled compound, available to the user, and the number of smdies being performed for which a development program is being provided, the intended end purpose of the compound, the mode of delivery or the task being perfonned using the compound, among other parameters .
  • the first computer storage medium also stores educational text, in particular definitions of the present invention, instractional text of the present invention and information for the calculation of safety margins.
  • Such information is stored in the form of HTML text.
  • the safety margin calculation information is in the form of HTML text.
  • the safety margin calculation information comprises a range of safety margin values based on information from completed toxicology and clinical smdies, whether the therapeutic indication being treated is life-threatening or not and/or if the toxicology is acute, subacute or chronic.
  • the range of safety margin values is from a value of about 1 to a value of about 10,000, in which 1 represents the lowest value for unreasonable safety and 10,000 represents the highest value for reasonable safety.
  • the value for unreasonable safety ranges from about 1 to about 100 and the value for reasonable safety ranges from about 101 to about 2000.
  • the value for unreasonable safety ranges from about 1 to about 10 and the value for reasonable safety ranges from about 11 to about 100. More preferably, the value for unreasonable safety is less than 10 and the value for reasonable safety is greater than 10 for subacute and chronic toxicity studies, and the value for unreasonable safety is less than 100 and the value for reasonable safety is greater than 100 for acute toxicity studies.
  • the ranges of safety margin values can be modified based on information developed in the art.
  • the safety margin value will be based on data entered by user.
  • the numerical value for the highest intended human clinical dose is taken from data entered by user on the intended clinical program development form wherein user indicates the highest dose of the bioactive compound the user intends to administer to an individual during a development program.
  • the denominator represents 70 kilograms.
  • the highest toxicology smdy dose is taken from data entered by user in either the subacute, acute or chronic toxicology development form, wherein user indicates the highest dose of bioactive compound user intends to administer in a particular toxicology smdy.
  • the system After calculating the safety margin value, the system automatically compares the value with the range of safety margin values stored in the first computer storage medium to determine if the safety margin for the data entered by user is reasonable or unreasonable. The system then stores that information and displays the calculated value as output.
  • Information entered by user using a development form is stored in an input table on the first computer storage medium.
  • Data from the input table is processed by the system and the resulting processed user input development data is stored in an output table.
  • processed user input development data that provides conflict information is derived from comparisons between data entered by user on different development forms.
  • processed user input development data that provides safety margin values is derived from comparisons between data entered by user on different development forms or from comparisons between data entered by user on one or more development forms and the financial table or the materials quantity table.
  • Development program output of the present invention is stored in the output table and displayed to user.
  • the development program output includes cost, time, materials, conflicts and safety margin values.
  • the development program output automatically adjusts to new processed user input development data generated when user enters new data or modifies existing data. Thus, user may alter data in a development form and view the effect of that alteration on the development program output thereby making the system iterative.
  • a system of the present invention further comprises a second computer storage medium that comprises a database comprising one or more tables selected from the group consisting of scientific literature table, a published clinical literature table and a stracmral table.
  • FIG. 22 depicts the software routine for the input and output of data using an embodiment of the data processing system according to the present invention.
  • This example describes entries and selections that may be made by user when designing a development program for a selective serotonin reuptake inhibitor involving pediatric patients.
  • the First Pass program is an interactive tool that allows the Sponsor to create customized preclinical development programs that outline those smdies that could be used to screen a specific compound or family of compounds up through those smdies necessary for a successful I vestigational New Drag (IND) Application.
  • the resulting development plan includes estimated costs, amount of material required and timelines for each smdy and identifies those smdies that are on the critical path of the development program.
  • First Pass instructs the user as to how to develop efficient preclinical development plans that consider factors such as:
  • the user entered information related to the intended clinical trial on the Intended Clinical Program Form shown below as Table 5.
  • ADME Absorption, Distribution, Metabolism and Excretion
  • the Sponsor may want to consider conducting an Expanded Acute Toxicity Study (proceed to Acute Toxicology Page after sending this form)
  • the user then accessed the ADME instructional text page, shown below as Text Box 2, consulted the page and then selected the metabolism instractional text page, shown below as Text Box 3.
  • the user selected the In Vitro Metabolism Form, shown below as Table 6, and selected metabolic stability and metabolite identification smdies using microsomes from the CD- 1 mouse and the beagle dog.
  • PK smdies are generally designed to characterize a drag's kinetic properties at therapeutic doses, whereas toxicokinetic (TK) data are collected at high doses (during toxicology smdies) associated with toxic effects.
  • TK smdies have to be conducted according to GLP but PK smdies are not required to be GLP studies.
  • the objectives of preclinical pharmacokinetic and absorption, distribution, metabolism, and excretion studies are to:
  • VD Volume of Distribution
  • Metabolism studies are not typically needed for a protein product since the metabolic pathway of protein is well understood: the protein will be broken down into its constituent amino acids. Thus, neither mass balance or classical biotransformation smdies are required. Tissue distribution information maybe important, especially if it helps you to understand if the protein is getting to the desired tissue. However, it is important to understand the fate of a hormone. Hormones are typically processed in a very controlled manner by a specific protease and can be cleaved to smaller, active fragments. References to publications describing this process should be included in your regulatory submission. Pharmacokinetic and bioanalytical studies that determine the ratio of intact to smaller fragments across all species, including man, are very important since they allow the Sponsor to argue for toxicological coverage. If you wish to design a pharmacokinetic smdy, please proceed to the absorption form.
  • Metabolic prediction studies use computational software packages and/or manual correlation with known metabolic profiles of existing compounds and can be helpful in a variety of areas. For instance, prediction of experimental compounds as potential specific cytochrome P450 isozyme substrates/inhibitors/inducers can help narrow the choice of isozymes to be examined during in vitro and in vivo studies. In addition, prediction of metabolite stracmres can both assist in metabolite identification during analytical method development studies and flag putative metabolites as toxicological agents.
  • liver microsomes/S9 subcellular fractions offer a convenient way to smdy a compounds metabolic profile, examine potential drag-drag interactions, and compare species-specific metabolic rates.
  • CYP450 systems are used during lead optimization/SAR smdies to rapidly identify specific cytochrome P450 substrates and inhibitors. Some of these systems also express cofactors (e.g., NADPH) and are also self-sufficient.
  • cofactors e.g., NADPH
  • Sponsors typically assess the metabolic stability of compounds using human, microsomes and determining loss of parent. Less than 20% loss at 60 minutes is considered favorable.
  • Metabolism information in a Phase I IND usually includes metabolic stability in toxicology species (including single-dose pharmacokinetic smdies), identification of main metabolites (as Ml, M2, and not necessarily identified and characterized), identification of metabolizing cytochrome P450s, and induction/inhibition information.
  • toxicology species including single-dose pharmacokinetic smdies
  • main metabolites as Ml, M2, and not necessarily identified and characterized
  • identification of metabolizing cytochrome P450s identification of metabolizing cytochrome P450s
  • induction/inhibition information e.g., if the intended first clinical study will enroll patients who could be taking multiple medication (e.g., AEDs or cancer patients), detailed metabolic profiling and drug-drag interaction studies should be conducted to ensure safe use of the compound in the clinic, h those instances where the metabolic pathway of one drug is sufficiently different from that of another, the Sponsor may be able to rationalize not conducting combination toxicology smdies.
  • Enzyme inhibition studies assess the potential of a compound to inhibit cytochrome P450 enzymes responsible for the metabolism of other drags. These studies can be conducted using microsomes and S9 fractions and known substrates of various cytochrome P450 enzymes. The data derived from such smdies include IC5 50 and approximate Kj. The K,- can then be compared to the anticipated (or known) therapeutic blood levels to determine if there is indeed a potential for drug-drag interactions.
  • Enzyme induction studies also provide information about the drug-drag interaction potential of your compound. Induction smdies typically require repeat-dosing in the live animals since induction typically results after 2-3 weeks of treatment. Thus, information regarding a compounds ability to promote enzyme induction can come from repeat-dose toxicology and/or pharmacokinetic smdies by extracting and testing the livers of treated animals. Assays such as effect on duration of phenobarbitone-induced sleep, and zoxazolamine-induced loss of righting reflex in the Primary Pharmacology section offer information regarding enzyme induction.
  • In vivo metabolism studies are conducted following intravenous and, if applicable, oral (or other) routes of administration and are termed pharmacokinetic smdies. These studies yield information regarding absorption and bioavailability (for non-iv administrations), half-life, metabolism, and pharmacokinetics in the live animal. It is not uncommon to see a high first pass effect in the rodent - this finding does not typically extrapolates to the human. It is important to know that differences can exist between in vitro and in vivo metabolic profiles (e.g., b-glucoronidation occurs only in vivo.) If you wish to outline an in vivo pharmacokinetic study, please go to the absorption form which captures information regarding single- and repeat-dose pharmacokinetic studies.
  • Toxicology is the smdy of adverse effects of chemicals on living organisms. Prior to initiating any clinical trials in the US, Sponsors are required to test their new compound in animal toxicology studies to ensure that the subjects/patients that will be exposed to the new compound will not have any harmful effects. The objective of toxicology studies is to identify and characterize the toxicities associated with administration of the new compound and it is disconcerting if a target organ of toxicity can not be identified. It is important to be able to determine the margin of safety between those doses that will be studied in the clinical program and the no-effect dose in animals (for non-life- threatening indications) or the dose that caused irreversible toxic effects or death in animals (for life- threatening indications). Doses described as per body surface area gives the most accurate assessment of doses given to animals relative to humans and, thus, provide the most conservative safety margins.
  • Acute/Expanded Acute (support single-dose human study) Subchronic/SubAcute. (typically ⁇ 90 days) Chronic(>90 days) Carcinogenicity
  • the user decided to conduct acute toxicity studies, as described in the text in Text Box 5, and proceeded to the Acute Toxicity Form, as shown in Table 7.
  • Two routes of administration were chosen: the intended clinical route (oral) and iv (required regardless of the intended clinical route). All standard assessments were chosen and no additional assessments or options were selected.
  • the system asked the user to initiate the nonrodent study simultaneous with the rodent study, after the in-life portion of the rodent study, or after the results of the entire rodent smdy were known. The user decided to wait until the entire study was completed.
  • Acute Toxicity is defined as the toxicity produced by a pharmaceutical when it is administered in one or more doses during a period not exceeding 24 hours.
  • the information obtained from these studies is useful in choosing doses for repeat-dose smdies, providing preliminary identification of target organs of toxicity, and, occasionally, revealing delayed toxicity.
  • Acute toxicity studies may also aid in the selection of starting doses for Phase I human studies and provide information relevant to acute overdosing in humans. For information related to acute toxicity testing for biological compounds, please go to Toxicology Studies for Biological Products.
  • Acute toxicity smdies in animals should be conducted using two routes of drag administration: 1) the route intended for human administration and
  • Acute toxicity studies may yield the following information:
  • NOEL no-effect level
  • MTD maximum tolerable dose
  • MNLD maximum non-lethal dose
  • the toxicity studies should be designed to assess dose- response relationships (and thus, would include doses lower than typicallyused in acute smdies) and pharmacokinetics.
  • Clinical pathology and histopathology should be monitored at an early time and at termination (i.e., for maximum effect and recovery).
  • ADME but less than what is typically in an IND; depends upon intended clinical use and population to be enrolled in clinical study
  • the user proceeded to the safety margin table, as shown in Text Box 6, and looked at the margin of safety built in to the preclinical program.
  • the table below presents the high dose anticipated in your clinical study and the highest doses that will be used in the supporting toxicology smdies and calculates safety margins to give you a very rough idea as to how much of a margin you have built in to your program.
  • the Sponsor should state the no effect levels (NOELS) determined in the toxicology studies and determine the safety margin between these levels and the starting dose in the clinical smdy.
  • NOELS no effect levels
  • the most conservative way to determine safety margins is via using body surface area (refer to Body Surface Area chart).
  • the starting dose in a Phase I dose-escalation smdy is either 1/lOth of that dose that cause sever, but reversible, toxicity in 1/lOth of the rodents (on a mg/m2 basis) or, if the toxicities were not reversible in the rodent, l/6th of the highest dose that did not cause severe toxicity in the non-rodent
  • Blood levels should be determined from toxicokinetic work and the relationship to adverse effects determined. Once clinical pharmacokinetic data have been collected and/or if human pharmacokinetic data have been modeled, safety margins should be discussed on the basis of drag levels rather than administered dose.
  • Subacute and subchronic toxicity are interchangeable terms referring to an experiment in which a drag is administered for a limited period usually 2-4 weeks up to 90 days.
  • a smdy of this type may serve one or more purposes:
  • Dose-ranging studies are typically conducted to determine the dose to be used in subchronic toxicity smdies. Throughout the test period the animals are observed for behavioral changes, the animal's general condition is noted, and food consumption and body weight are monitored. If indicated by the phamacologic profile of the drug (e.g., diuretic effect), water intake and urine output may require closer than routine attention. The animals are periodically subj ected to ophthalmological examination. Clinical pathology assessments (hematology, clinical chemistry, urinalysis) should be conducted periodically during the study and after the recovery period.
  • Routine tests may be supplemented or deleted as indicated by the known characteristics of the drag under study. At terminal sacrifice, organs and tissues are examined by the pathologist. Microscopic examination may confirm evidence of organ function changes noted while smdies were in progress or may reveal changes not reflected by tests perfonned during the course of the study. In evaluation of the results, the toxicologist must take into consideration a number of factors: • Severity of changes
  • a toxicologically relevant species defined as such via metabolism, pharmacoldnetic profiles or because of similar pharmacology to humans
  • NOEL no-effect level
  • the user outlined the subacute toxicology smdies on the Sub Acute Toxicity Form, as shown in Table 8.
  • the user chose to conduct both dose-range finding smdies (non-GLP) and pivotal GLP toxicology smdies in the CD-I rat and beagle dog using the oral route of administration, the intended clinical route. All standard assessments were chosen and no additional assessments or options were selected.
  • the user chose to initiate the subacute smdies after the in-life portion of the rodent smdy was complete.
  • the starting dose in a Phase I dose-escalation study is either l/10th of that dose that cause sever, but reversible, toxicity in l/10th of the rodents (on a mg/m2 basis) or, if the toxicities were not reversible in the rodent, l/6th of the highest dose that did not cause severe toxicity in the non-rodent.
  • Blood levels should be determined from toxicokinetic work and the relationship to adverse effects determined. Once clinical pharmacokinetic data have been collected and/or if human pharmacokinetic data have been modeled, safety margins should be discussed on the basis of drug levels rather than administered dose.

Abstract

L'invention concerne un système et un procédé permettant de fournir le programme de développement d'un composé bioactif. Ce système et ce procédé sont généralement mis en oeuvre sur un ordinateur, et comprennent un logiciel invitant un utilisateur à entrer des données de développement de façon à traiter les données de développement entrées par l'utilisateur, et à générer une sortie de programme de développement basé sur les données de développement entrées. Généralement, la sortie comprend des informations relatives au temps, au coût, et aux matériaux nécessaires pour réaliser ledit programme de développement.
PCT/US2001/003011 2000-02-01 2001-01-29 Systeme de traitement de donnees pour programmes de developpement de composes WO2001057760A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU34657/01A AU3465701A (en) 2000-02-01 2001-01-29 Data processing system for compound development programs
CA002398892A CA2398892A1 (fr) 2000-02-01 2001-01-29 Systeme de traitement de donnees pour programmes de developpement de composes
EP01906790A EP1261929A1 (fr) 2000-02-01 2001-01-29 Systeme de traitement de donnees pour programmes de developpement de composes

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US17951500P 2000-02-01 2000-02-01
US60/179,515 2000-02-01
US18520700P 2000-02-25 2000-02-25
US60/185,207 2000-02-25
US52136000A 2000-03-08 2000-03-08
US09/521,360 2000-03-08

Publications (1)

Publication Number Publication Date
WO2001057760A1 true WO2001057760A1 (fr) 2001-08-09

Family

ID=27391127

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/003011 WO2001057760A1 (fr) 2000-02-01 2001-01-29 Systeme de traitement de donnees pour programmes de developpement de composes

Country Status (4)

Country Link
EP (1) EP1261929A1 (fr)
AU (1) AU3465701A (fr)
CA (1) CA2398892A1 (fr)
WO (1) WO2001057760A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014107619A1 (fr) * 2013-01-04 2014-07-10 Second Genome, Inc. Indice de modulation du microbiome

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4002383A3 (fr) * 2020-11-13 2022-08-03 Tokyo Institute of Technology Dispositif de traitement d'informations, procédé de traitement d'informations, support d'enregistrement enregistrant le programme de traitement d'informations et système de traitement d'informations

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5657255A (en) * 1995-04-14 1997-08-12 Medical Science Systems, Inc. Hierarchical biological modelling system and method
US5777888A (en) * 1995-08-09 1998-07-07 Regents Of The University Of California Systems for generating and analyzing stimulus-response output signal matrices
US5965352A (en) * 1998-05-08 1999-10-12 Rosetta Inpharmatics, Inc. Methods for identifying pathways of drug action
US5978804A (en) * 1996-04-11 1999-11-02 Dietzman; Gregg R. Natural products information system
US6108635A (en) * 1996-05-22 2000-08-22 Interleukin Genetics, Inc. Integrated disease information system

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5657255A (en) * 1995-04-14 1997-08-12 Medical Science Systems, Inc. Hierarchical biological modelling system and method
US5657255C1 (en) * 1995-04-14 2002-06-11 Interleukin Genetics Inc Hierarchic biological modelling system and method
US5777888A (en) * 1995-08-09 1998-07-07 Regents Of The University Of California Systems for generating and analyzing stimulus-response output signal matrices
US5978804A (en) * 1996-04-11 1999-11-02 Dietzman; Gregg R. Natural products information system
US6108635A (en) * 1996-05-22 2000-08-22 Interleukin Genetics, Inc. Integrated disease information system
US5965352A (en) * 1998-05-08 1999-10-12 Rosetta Inpharmatics, Inc. Methods for identifying pathways of drug action

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014107619A1 (fr) * 2013-01-04 2014-07-10 Second Genome, Inc. Indice de modulation du microbiome

Also Published As

Publication number Publication date
AU3465701A (en) 2001-08-14
EP1261929A1 (fr) 2002-12-04
CA2398892A1 (fr) 2001-08-09

Similar Documents

Publication Publication Date Title
Adams et al. Estimating the cost of new drug development: is it really $802 million?
Polli et al. Summary workshop report: bioequivalence, biopharmaceutics classification system, and beyond
Charles The process of new drug discovery and development
Matoren The clinical research process in the pharmaceutical industry
Ishida et al. Ai-driven synthetic route design incorporated with retrosynthesis knowledge
Tanneau et al. Population pharmacokinetics of delamanid and its main metabolite DM-6705 in drug-resistant tuberculosis patients receiving delamanid alone or coadministered with bedaquiline
Xu et al. Predictive models for human cytochrome P450 3A7 selective inhibitors and substrates
Thayer et al. Systematic evidence map (SEM) template: Report format and methods used for the US EPA Integrated Risk Information System (IRIS) program, Provisional Peer Reviewed Toxicity Value (PPRTV) program, and other “fit for purpose” literature-based human health analyses
Griesenauer et al. CDEK: clinical drug experience knowledgebase
Rajpoot et al. In silico methods for the prediction of drug toxicity
EP1261929A1 (fr) Systeme de traitement de donnees pour programmes de developpement de composes
Rousseaux et al. Overview of drug development
Cavalla Modern strategy for preclinical pharmaceutical R&D: Towards the virtual research company
AU2005203547A1 (en) Data processing system for compound development programs
Steiner Clinical Development: Strategic, Pre-Clinical, and Regulatory Issues
Cronin Toxicological information for use in predictive modeling: Quality, sources, and databases
Choudhury et al. Virtual screening of phytochemicals
Zineh et al. The clinical pharmacogeneticist: an emerging regulatory scientist at the US Food and Drug Administration
Singer et al. Challenges and solutions for personalizing medicines
Haschek et al. Haschek and Rousseaux's Handbook of Toxicologic Pathology, Volume 2: Safety Assessment and Toxicologic Pathology
Castro-Pastrana et al. Drug safety approaches in anti-infective drug discovery and development
Musikaphongsakul et al. Development of a physiologically based pharmacokinetic (PBPK) model of psilocybin and psilocin from magic mushroom in rats and humans
Otavi et al. Quantitative extrapolation interspecies scaling/low-dose extrapolation
Lübbert 13 Drug development and registration
Gibson Aiding candidate drug selection: introduction and objectives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2398892

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 34657/01

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2001906790

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2001906790

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Ref document number: 2001906790

Country of ref document: EP