AU3465701A - Data processing system for compound development programs - Google Patents

Description

WO 01/57760 PCT/USO1/03011 DATA PROCESSING SYSTEM FOR COMPOUND DEVELOPMENT PROGRAMS FIELD OF THE INVENTION 5 The present invention relates to a dataprocessing system for providing a development program for a bioactive compound. In particular, 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. 10 The system also detennines safety margins for a development program. BACKGROUND OF THE INVENTION The pharmaceutical and agricultural industries have developed technology that yields hundreds of thousands of chemical compounds in a rapid timeframe. The development of 15 high throughput screening techniques enables such industries to quickly identify the most potent biologically active compounds from amongst those compounds. Regulatory agencies such as the Food and Drug Administration (FDA) and the United States Department of Agriculture (USDA) have instituted guidelines aimed at increasing the rate and number of compounds that advance to testing in animals, such as guidelines for acute toxicity testing 20 to support single-dose studies in a clinic or guidelines for in vitro drug metabolism and interaction studies in the drug development process. The FDA has also established new types of applications, such as Screening Innovative New Drugs (INDs) applications, to increase the speed of the drug approval process. These industry and government agency efforts to get more products to market, 25 however, are overshadowed by the low success rate of compounds in the preclinical phase of development. It has been reported that as low as 1% to 5% of the compounds tested reach the market (Lehman Brothers, 1997). It has been estimated that for every five thousand compounds that enter the preclinical phase of development, only two hundred and fifty will make it to the next phase of development (Phase I) and only one compound will progress to 30 a New Drug Application (NDA) for marketing approval by the FDA (PhRMA). The low clinical success rate has made late stage development of a drug and other bioactive compounds costly and time consuming. 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 WO 01/57760 PCT/USO1/03011 2 likelihood of success in a development program. There are numerous reasons for failure of a compound in development. For example, 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 5 pharmacological effects. Thus, there is a need for improved systems for designing compound development programs that address factors that may influence the success of a development program. SUMMARY OF THE INVENTION 10 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 15 provided by developer, the system analyzes such information relative to studies typically required for development and provides, for example, time, cost, quantity ofmaterial, 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 20 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 25 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. In particular, the data processing system provides software for prompting a user to input certain specified development data, including for example 30 information regarding chemical properties, intended use, pharmacology, toxicology, safety pharmacology, and technical and patent publications. The system determines time, cost and WO 01/57760 PCT/USO1/03011 3 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 5 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 10 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 15 said computer processor for storing computer software and data. In this embodiment, 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. In this embodiment, the system also includes software for prompting a user to input development data for a purpose selected from the group consisting of evaluating the 20 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 25 the input development data: The output includes an output selected from the group consisting of time, cost, quantity of materials, and conflicts. Finally, in this embodiment, 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 30 to input development data, processing the user input development data, and generating a development program output based on said input development data.

WO 01/57760 PCT/USO1/03011 4 BRIEF DESCRIPTION OF THE DRAWINGS 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 5 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 Fonm. 10 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. 15 Fig. 11 is an example of an In Vitro Metabolism Form. Fig. 12 is an example of a Drug-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. 20 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. 25 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. 30 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.

WO 01/57760 PCT/USO1/03011 5 DETAILED DESCRIPTION OF THE INVENTION The present invention includes a data processing system and method for providing a development program for a bioactive compound. As used herein, providing a development program refers to determining, identifying, defining, analyzing or proposing a development 5 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 11 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 II(b) studies. 10 The system of the present invention is particularly suited for analysis of preclinical development programs, and more specifically, programs including the steps needed for a Phase I IND filing. 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 15 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 20 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 25 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 30 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 WO 01/57760 PCT/USO1/03011 6 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 5 during completion of various development program options. According to the present invention, steps to complete various development program options include, for example, determining dosing requirements, performing in vitro assays or testing in animal models. User enters the system at a session entry point. Such entry point can include software that secures the session by prompting user to enter certain identification information such as 10 user identification information (User ID), password information (Password), session identification information (Session ID), date infonnation (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 15 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. Such regulatory agencies include, for example, the FDA, USDA, Environmental Protection Agency (EPA) and foreign equivalents thereof. Preferably, the 20 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 infonnation sites of the present system include Definitions, Reference Databases and Useful Links. The system displays 25 information contained at each information site. In a preferred embodiment, 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. 30 Information is made visible to user as HTML text. Generally such educational text includes information defining a variety of regulatory, pharmacokinetics, pharmacology, chemistry, toxicokinetic, toxicology, metabolism or drug development terms. Such information is based WO 01/57760 PCT/USO1/03011 7 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, cytochrome P450, distribution, 5 drug substance, drug drug interactions, ERC, excretion, excretion-balance, study, 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 Inactivation of IND, reversible toxicities, SAR, S9 subcellular fractions, 10 safety margin, Segment I, Segment II, Segment III, sensitive species, subacute/subchronic toxicity, teratogenicity, toxicokinetics, toxicologically relevant species, transspecies carcinogen and/or viability index. One of skill in the art will recognize that educational text may be added or modified over time based on changes in the compound development field. Educational text is visible to user during any point in the system through the lefthand frame 15 shown in Fig. 2 that can contain a definitions index and educational text. For example, if the user selects definitions regarding IND or NDA filings, the system can display appropriate text, such as text for an IND filing as shown in Table 1: TABLE 1 20 IND: Investigation New Drug 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 25 subjects/patients. Investigation New Drug Application The contents of an IND (per 21 CFR 312.23) are as follows: 30 Item IND Sections 1 Cover Letter, Form FDA-1571 2 Table of Contents 3 Introductory Statement and General Investigative Plan 35 4 General Investigative Plan WO 01/57760 PCT/USO1/03011 8 Item IND Sections 5 Investigator Brochure 6 Protocol and Investigator information section 7 Chemistry, Manufacturing, and Control Information 8 Pharmacology and Toxicology Information 5 9 Previous Human Experience Section 10 Additional Information Also in a preferred embodiment, a user may proceed from the starting point to the Reference Databases site where user may access one or more databases that include, for 10 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 NIH's PubMed site, the United States Patent 15 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 20 be deleted or added as needed. Following successful entry into the system, the user may also choose to proceed from the session entry to a data entry site. At these sites, user is queried in such a manner that user selects or enters information specified by the system. Such information input by user is referred to herein as development data. Development data input by user at the data entry site 25 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 30 information to the development data processor. Following execution of the data entry, data WO 01/57760 PCT/USO1/03011 9 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 5 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 10 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 ofthe compound, selecting safety pharmacology studies, evaluating toxicology and/or evaluating information in the published scientific or patent literature. 15 At the data entry site, 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 20 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 25 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 30 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 WO 01/57760 PCT/USO1/03011 10 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. Preferably, the system prompts 5 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 10 main menu lists the various sites of the system that can be accessed by user. In a preferred embodiment, 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 15 proceeds to the appropriate site when the user enters a menu choice. If 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 20 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 25 and then proceeds to the development form selected by user. If 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 byuser. Each instructional text page prompts user to select the development form 30 related to that topic. As such, more than one form may be accessed from an instructional text page because the topics are related. Once user has selected a development form, the system asks the user to select or enter certain data and the user proceeds with data entry. The system WO 01/57760 PCT/USO1/03011 11 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. In a preferred embodiment, a system of the present invention displays instructional 5 chemistry text that explains the type of chemical information user will need to provide a development program and the importance of such information. Instructional 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. 10 In a preferred embodiment, a system of the present invention displays instructional 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 15 therapeutic indication, to known drugs 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. In a preferred embodiment, a system of the present invention displays instructional 20 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. 25 In a preferred embodiment, a system of the present invention displays instructional ADME/PK text that explains the different types of ADME or PK information that is useful to obtain during a development program, including, for example, absorption (extravascular routes), bioavailability (iv = 100% bioavailability), vehicle and food effects, distribution, plasma protein binding, tissue distribution, volume of distribution (VD), metabolism, 30 first-pass effects, major metabolites/pathways, saturation, activity of metabolites (with respect to both pharmacological activity and toxicity, excretion or major route and drug clearance).

WO 01/57760 PCT/USO1/03011 12 In particular, instructional 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. In addition, instructional ADME/PK text may also contain text that explains the significance 5 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. Moreover, instructional ADME/PK text may also contain text that explains the importance of performing metabolism studies, describes Phase I IND requirements, describe different drugs that induce, inhibit or are substrates for specific 10 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 drug-drug interactions, compare species-specific routes of elimination, or facilitate the lead optimization process. Examples of metabolic studies suitable for a development program 15 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. Moreover, instructional ADME/PK text may also contain text that explains that a variety of mechanisms 20 by which drugs 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. In a preferred embodiment, a system of the present invention displays instructional 25 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, 30 cardiovascular/respiratory, gastrointestinal, genitourinary, endocrine, anti-inflammatory, immunoactive, chemotherapeutic, enzyme effects or behavioral activity, or drug interaction WO 01/57760 PCT/USO1/03011 13 studies such as studies using pentobarbitone- and/or zoxazolamine or in vitro tests using cytochrome P450 isozymes. In a preferred embodiment, a system of the present invention displays instructional toxicology text that explains the purpose and importance of performing toxicology studies, 5 provides information regarding different types of toxicology studies including their duration, when they are performed during a development program, the results observed from such studies and special circumstances that might arise during a development program that require particular toxicology steps. Instructional toxicology text can also include information regarding different types of toxicology studies needed for a Phase I IND including, for 10 example, acute /expanded acute studies, subchronic/subacute (typically <90 days) studies or genotoxicity studies. The instructional 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 15 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. Instructional 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 20 or are not applicable to biological products including, for example, chronic studies, genotoxicity studies, reproductive toxicology studies or carcinogenicity studies. In a preferred embodiment, a system of the present invention displays instructional subacute toxicology text that explains when subacute toxicity studies are useful and the type of information that can be derived from such studies. As used herein, "subacute" and 25 "subchronic toxicity" are interchangeable terms referring to an experiment in which a drug is administered for a limited period usually 2-4 weeks up to 90 days. In a preferred embodiment, a system of the present invention displays instructional chronic toxicology text that explains the design and factors affecting the duration of chronic toxicity studies. As used herein, toxicity studies of a duration longer than 90 days are 30 referred to as "chronic." In a preferred embodiment, a system of the present invention displays instructional carcinogenicity studies for toxicology text that explains when carcinogenicity studies need WO 01/57760 PCT/USO1/03011 14 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 5 (CAC) of the FDA. In a preferred embodiment, a system of the present invention displays instructional 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. 10 In addition, instructional genotoxicity text can contain information regarding chemical structures related to the carcinogenic and/or mutagenic potential of chemicals. In a preferred embodiment, 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 studies that can be used to test for 15 reproductive toxicity including, for example, fertility and general reproductive performance studies, teratogenicity studies, perinatal and postnatal studies that determine the effects of a compound on the suckling and lactating dam and the development of the newborn or multigenerational studies that investigate the effects of the drug throughout a number of generations. The instructional reproductive toxicology text can also contain information 20 regarding the timing of such studies and interpretation of results obtained from such studies. In a preferred embodiment, a system of the present invention displays instructional special toxicity text that explains when special toxicity studies need to be performed and the types of studies that are useful in a development program, such as dermal irritation studies to test topical products, dermal sensitization studies for products that will come in contact 25 repeatedly with the skin, ophthalmic irritation studies for opthamological products, ototoxicity studies for otic preparations or vascular irritation studies for intravenous formulations. Upon submission of data in a development forn, the data automatically passes to the value calculation software module and the system displays the time, cost and materials 30 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 WO 01/57760 PCT/USO1/03011 15 program. Also, the time data displays the amount of time for individual activities, as well as the relative order or overlap of individual activities. Preferably, 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 5 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. If 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. One of skill in the art 10 will recognize topics related to primary pharmacology. Preferred topics include antiinfectives, AIDS/HIV, hepatitis, analgesics, Alzheimers, vaccines, antirheumatic disease therapy, obesity, immunomodulators, oligonucleotides, oncology, osteoarthritis, osteoporosis and topical microbicides. Upon selection by user of a particular topic, the system proceeds to a site containing information about the topic and displays such information. Preferably, 15 primary pharmacology information contains information regarding background information about primary pharmacology, and when and why primary pharmacology studies are performed. In particular, a system of the present invention displays text about antirheumatic disease therapy that describes the types of studies that can be performed when developing an 20 antirheumatic disease therapy including, for example, pharmacokinetic studies, 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 studies including reproductive toxicity studies, or studies useful for selecting compounds that inhibit cells and processes 25 responsible for rheumatoid arthritis. In particular, a system of the present invention displays text about antiinfectives that contains information related to particular organisms and the diseases they cause. In particular, 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 30 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 WO 01/57760 PCT/USO1/03011 16 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. 5 In particular, 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. In particular, a system of the present invention displays text about Alzheimers Disease including information about tests typically conducted for Alzheimer's products. Such tests 10 include, for example, passive avoidance tests, eight-arm radial maze tests, or Morris Water Maze tests. In particular, a system of the present invention displays text about oncology that explains the need for and describes suitable studies for developing an anti-cancer product, such studies including, for example, cell culture assays to assess cytotoxicity, nude mouse 15 human xenograft models, nude mouse models to assess potential for a compound to inhibit metastasis, cytotoxicity studies with non-cancer cells, twenty-eight-day toxicity studies, genotoxicity studies, toxicology studies of longer duration if clinical studies of greater than 28 days are required for the development program, carcinogenicity studies, or combination toxicity studies. 20 In particular, a system of the present invention displays text about osteoporosis that explains the need to perform studies 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 studies. 25 In particular, 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. In particular, a system of the present invention displays text about immunomodulators 30 that explains the need to provide evidence of immunomodulatory activity of an anti-HIV compound prior to initiating clinical studies including, for example, characterizing the WO 01/57760 PCT/USO1/03011 17 mechanism of action, safety profiling, antiviral activity is distinct from any cytotoxicity or information regarding how immunomodulators work. In particular, a system of the present invention displays text about oligonucleotides that explains toxicology issues associated with antisense compounds including, for example, 5 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 studies or bone marrow purging. In particular, a system of the present invention displays text about osteoarthritis that 10 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 studies 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. 15 In particular, 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 studies, formulation testing, or toxicology requirements. 20 When user has entered data for two or more forms, 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 25 conjunction with the time, cost, materials quantity output, such as shown in Fig. 23. In one example, 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 studies are indicated on the Chronic Toxicity Form; the intended clinical study entered by user on an Intended Clinical Program Form 30 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 drug in juvenile or elderly animals, respectively; or the intended clinical study entered by user on an Intended Clinical WO 01/57760 PCT/USO1/03011 18 Program Form will enroll female or male subjects only but the toxicology studies 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 5 can include clickable links to other relevant sections of the program, such as the following shown in Table 2: TABLE 2 The system has determined that the selections made for the toxicology studies 10 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 studies. Please make the necessary 15 changes here. This will update the studies concerned. Length of Duration from Sub Acute Tox Length of Duration from Intended 20 Clinical Program From Sub-Acute Tox From Intended Clinical Program Juvenile Animals Pediatric Population Elderly Animals Elderly (>65 years) 25 In addition, if GMP ("Good Manufacturing Practice") material needed for all preclinical studies as calculated by the system using data entered by user on an Acute Toxicology Form, Sub-Acute Toxicology Form, Chronic Toxicology Form, Absorption Studies Form, Distribution Studies Form, Drug-Drug Interaction Form, In Vitro Metabolism Studies Form, Excretion Studies Form, Safety Pharmacology Studies Form, Carcinogenicity 30 Studies Form, Special Toxicology Studies Form, Genotoxicity Study Form and/or Reproductive Toxicology Studies Form exceeds GMP material available entered by user on a Chemistry Form, the system displays text indicating that the user does not have enough GMP material to conduct the studies selected. The same occurs with non-GMP material and non-GLP preclinical studies as calculated from Acute Toxicology Form, Sub-Acute 35 Toxicology Form, Chronic Toxicology Form, Drug-Drug Interaction Form, In Vitro WO 01/57760 PCT/USO1/03011 19 Metabolism Studies Form, Carcinogenicity Studies Form, Special Toxicology Studies Form, Reproductive Toxicology Studies Form, and/or Lead Optimization Form. Moreover, if pharmacokinetic studies outlined by the user on an Absorption Form require radiolabeled drug but the user has not indicated they have any radiolabeled drug on 5 a Chemistry Form or user has not indicated that they need radiolabeled drug made on an Absorption Form, then the system displays text that indicates to the user that there is a discrepancy. Also, if user makes the following selection on an Absorption Form: "Use repeat-dose toxicology study to generate data for repeat-dose pharmacokinetic profile", but no repeat 10 dose toxicology study has been selected by user on a Sub-Acute Toxicology Form, then the system displays text that instructs 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. In addition, if user makes the following selection on a Drug-Drug Interaction Form: 15 "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. 20 Moreover, if the user inputs the term "oligonucleotide" into the class of compound on an Intended Clinical Program Form and a monkey acute toxicity study 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. 25 Also, if the user inputs information on a Toxicology instructional text page indicating that user is using the development program being provided by the system for a Phase I IND 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, or a Safety Pharmacology Form, then the 30 system displays text asking if the user want to go back to any of these forms. Or, if the user inputs information on a Toxicology page indicating that user is using the development program being designed or evaluated by the system for a Phase II IND and no studies are WO 01/57760 PCT/USO1/03011 20 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 Drug-Drug 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 5 of these forms. Or, if the user inputs information on 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 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 Drug-Drug Interaction Form, a 10 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. Or, if the user inputs information on 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 15 Genotoxicity Form, an Absorption Form, a Distribution Form, an Excretion Form, an In Vitro Metabolism Form, a Drug-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 forms. The conflicts described herein are intended to be examples of conflicts. One of skill in the art will recognize that 20 additional conflicts may be added to the system based on technical requirements of studies within a development program. Upon entry of data by a user into a development form, 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. Ifuser 25 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 30 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.

WO 01/57760 PCT/USO1/03011 21 In a preferred embodiment, 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 studies being performed. An example of a safety margin output displayed by the system is shown in Table 3. An example 5 of how to convert an amount per body weight dose to body surface area is shown in Table 4. TABLE 3 Highest High dose High dose High dose Safety 10 anticipated from acute from from chronic Margin clinical toxicology subacute toxicology (based dose studies toxicology studies (mg/kg) on high (mg/kg) (mg/kg) studies doses) (mg/kg) Acute Subacute Chronic 15 N/A 1000 N/A N/A N/A N/A N/A TABLE 4 20 Body Surface Area Calculations To convert a mg/kg dose to a body surface area dose, multiply the mg/kg dose by the conversion factor in kg/m 2 . For example, a 10 mg/kg dose is 10 x 37 or 370 mg/m 2 . 25 Species Body Weight (kg) Surface Area ( 2 ) Conversion factor Mouse 0.02 0.0066 3.0 Rat 0.15 0.025 5.9 Monkey 3.0 0.244 12.3 30 Dog 8.0 0.0404 19.8 Human 60 1.62 37 Refer to the Toxicology page for a table that displays conversion factors that allow you to determine comparable mg/kg doses across species, assuming equivalent surface area doses. 35 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 WO 01/57760 PCT/USO1/03011 22 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 5 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 10 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 15 program options; or the safety margins based on dose and toxicity. According to the present invention, steps to complete various development program options include, for example, determining dosing requirements, performing in vitro assays or testing in animal models. Development program options refers to different possible studies that can be performed for any given therapeutic indication. In addition, the first storage medium stores the User ID, 20 Password, Session ID and Date information entered by a user. In particular, 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. For example, the temporal table contains information that the time 25 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 30 compound needed to complete a certain task in a development program. For example, the materials quantity table contains information that the amount of material typically needed for WO 01/57760 PCT/USO1/03011 23 a single dose study is a certain gram amount while a long term study may require four times that amount. It is within the scope of the present invention that data contained in the tables of the first computer storage means can be modified or updated over time. Among other 5 parameters, 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 study, overhead, equipment and personnel 10 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 studies 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 performed using the compound, among 15 other parameters. The first computer storage medium also stores educational text, in particular definitions of the present invention, instructional text of the present invention and information for the calculation of safety margins. Such information is stored in the form of HTML text. In particular, the safety margin calculation information is in the form of HTML 20 text. The safety margin calculation information comprises a range of safety margin values based on information from completed toxicology and clinical studies, whether the therapeutic indication being treated is life-threatening or not and/or if the toxicology is acute, subacute or chronic. In one embodiment, 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 25 and 10,000 represents the highest value for reasonable safety. In another embodiment, 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. Preferably, 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 30 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 WO 01/57760 PCT/USO1/03011 24 than 100 for acute toxicity studies. One of skill in the art will recognize that 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 formula used by the system is as follows: 5 Highest Intended Human Clinical Dose + 70 = X milligrams/kilogram Highest Toxicology Study Dose + X = safety margin value 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 10 during a development program. The denominator represents 70 kilograms. The highest toxicology study 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 study. After calculating the safety margin value, the system automatically compares the 15 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 20 the resulting processed user input development data is stored in an output table. Preferably, processed user input development data that provides conflict information is derived from comparisons between data entered by user on different development forms. Preferably, 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 25 comparisons between data entered by user on one or more development forms and the financial table or the materials quantity table. Development program output ofthe 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 30 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.

WO 01/57760 PCT/USO1/03011 25 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 structural table. 5 A preferred embodiment of the present invention is illustrated in Fig. 22 which depicts the software routine for the input and output of data using an embodiment of the data processing system according to the present invention. The following examples are provided for the purposes of illustration and are not intended to limit the scope of the present invention. 10 EXAMPLES Example 1 This example describes entries and selections that may be made by user when designing a development program for a selective serotonin reuptake inhibitor involving 15 pediatric patients. The user entered a User ID, Session ID, Password and Date. The system displays the welcome page shown below, as Text Box 1. 20 Text Box 1 Introduction Chemistry Lead Optimization Program 25 Supporting the Clinical program Lead Profile/Preclinical Program Primary Pharmacology ADME/PK 30 Safety Pharmacoloav Toxicology Definitions Search First Pass 35 Database Query Back Form Links Home Useful Links WO 01/57760 PCT/USO1/03011 26 Text Box 1, cont. Welcome to First PassTM 5 The First Pass program is an interactive tool that allows the Sponsor to create customized preclinical development programs that outline those studies that could be used to screen a specific compound or family of compounds up through those studies necessary for a successful Investigational New Drug (IND) Application. The resulting development plan includes estimated costs, amount of material required and timelines for each study and 10 identifies those studies 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: 15 - The route of administration in the clinic; - The indication (e.g., fewer toxicology studies are required for life-threatening disease than for non-life-threatening disease); - The mechanism of action of the drug or class; - The structure of the compound or family of compounds; 20 - Whether the drug or class is novel or similar to another compound on the market; - The duration of the proposed clinical study; - The population to be enrolled in the proposed clinical study; - Whether the compound is a drug or biologic; and when the synthesis is established; - The impurity profile of the compound. 25 First Pass creates preclinical development plans that consider the intended clinical program and the acceptable/unacceptable risks, the mechanism of action and issues around predicted mechanism- based toxicities, and the "typical" reason drugs fail during the pre-IND phase. This approach allows the Sponsor to prioritize compounds and move them in to the clinic 30 faster and with a greater probability of success. The user entered information related to the intended clinical trial on the Intended 35 Clinical Program Form, shown below as Table 5. In this example, the user proceeded to the Absorption, Distribution, Metabolism and Excretion (ADME) page and chose to outline metabolism studies using the In Vitro Metabolism Form to help determine the relevant toxicological species.

WO 01/57760 PCT/USO1/03011 27 Table 5 Your Session ID is test and your Session Title is new one 5 Any changes you submit will overwrite this sessions data! If you are using First PassTm to outline a pre-clinical development program that will support a clinical program, please complete the following: Class of Compound (please 10 specify, e.g., SSRI, antibody, I SSRI muscarinic antagonist) Indication (please specify) depression Information regarding the intended clinical study Lowest dose anticipated 1 mg 15 Highest dose anticipated _10_ _ mg Duration of Treatment* 1 to 7 day Population (check all that apply): Healthy volunteers I Patients Males I Females J[Eil 20 Pediatric population Z Elderly (>65 years) El What information will you collect: (check all that apply) Pharmacokinetics I [ Safety and tolerability Maximum tolerated dose I Pharmacodynamics please specify | . 25 PPD has worked with Sponsors to devise novel "First Time in Human" clinical studies that include efficacy or pharmacodynamic assessments so that the Sponsor can get an early indication as to the 0 potential for the compound to work. Would you like PPD to work with you to develop a clinical protocol or program? _ _ 30 Note: If information regarding the population and the anticipated dose is not entered, potential conflicts between the preclinical and clinical programs can not be identified by FIRST PASS. *If the intended clinical study will be a single-dose study, the Sponsor may want to consider conducting an Expanded Acute Toxicity Study (proceed to Acute Toxicology 35 Page after sending this form) WO 01/57760 PCT/USO1/03011 28 The user then accessed the ADME instructional text page, shown below as Text Box 2, consulted the page and then selected the metabolism instructional text page, shown below as Text Box 3. After consulting the metabolism instructional text page, the user selected the In Vitro Metabolism Form, shown below as Table 6, and selected metabolic stability and 5 metabolite identification studies using microsomes from the CD-I mouse and the beagle dog. Text Box 2 ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION (ADME) 10 ADME Studies for Drugs There are no specific U.S. regulations defining the scope of preclinical pharmacokinetic and toxicokinetic studies. However, several guidance documents, recently finalized under the 15 auspices of the international conference on harmonization of technical requirements for human use (ICH) provide guidance on the application of pharmacokinetic and toxicoldnetic data to the preclinical program. "The ICH approach is intentionally nondetailed to allow for flexibility in study design and to ensure that kinetic endpoints will be study- and drug-specific without impeding collection of adequate and accurate toxicity data." 20 Pharmacokinetic (PK) studies are generally designed to characterize a drug's kinetic properties at therapeutic doses, whereas toxicokinetic (TK) data are collected at high doses (during toxicology studies) associated with toxic effects. Thus, TK studies have to be conducted according to GLP but PK studies are not required to be GLP studies. The 25 objectives of preclinical pharrnacokinetic and absorption, distribution, metabolism, and excretion studies are to: (1) characterize the relationship between drug dosage, exposure, and response; (2) provide data for interpretation of results of preclinical toxicity studies; 30 (3) support the design of subsequent preclinical toxicity and toxicokinetic studies; (4) provide data for the design of early clinical trials in man; and ultimately to (5) provide safety information for the package insert. The main items of interest are: 35 - Absorption (extravascular routes) - Bioavailability (iv = 100% bioavailability) - Vehicle, food effects - Distribution 40 - Plasma protein binding * Tissue distribution - Volume of Distribution (VD) - Metabolism - First-pass effects WO 01/57760 PCT/USO1/03011 29 - Major metabolites/pathways - Saturation - Activity of metabolites (with respect to both pharmacological activity and toxicity; may not know answer until later in development) 5 - Excretion - Major route and drug clearance (CL, CL/F) Optimally, findings from preclinical pharmacokinetic and toxicokinetic studies can enable one to estimate the relationship between drug dosage and the safe toxic plasma concentration 10 range in human. Thus, to use blood-level data to adjust the clinical dose, the Sponsor will need to determine if there are any species or gender differences with respect to ADME of the drug. This information can be obtained from toxicology studies and metabolism studies (note that some CYP450 enzymes are sex-specific). However, that may not always be possible since there can be species-dependent effects that do not extrapolate to humans. 15 At one time, the only ADME information submitted in a Phase I IND included: - Single-dose pharmacokinetics (absorption) - Repeat-dose pharmacokinetics (absorption) 20 - Whole body autoradiography (distribution) - Mass balance studies (excretion) - Preliminary information regarding major metabolites from pharmacokinetic studies 25 If the Sponsor will enroll patients in Phase I studies who are taking numerous medications, more extensive metabolism work should be done much earlier in the program to support safe use of the compound in such a clinical study. Absorption 30 Distribution Metabolism Excretion 35 Text Box 3 Metabolism It is important to learn early in development whether a compound is eliminated by excretion 40 of unchanged drug or by one or more routes of metabolism. When elimination occurs primarily by metabolism, the routes of metabolism can significantly affect a drug's safety and efficacy. Most tissues have some drug metabolizing capacity but the liver is by far the most important organ, on the basis of size if not always concentration of drug metabolizing enzymes. 45 WO 01/57760 PCT/USO1/03011 30 Metabolism studies are designed to identify the cytochrome P450 enzymes responsible for transforming a development candidate into one or more active or inactive metabolites, identify potential drug-drug interactions, compare species-specific routes of elimination, and facilitate the lead optimization process. The studies described herein offer one approach to 5 developing information about drug metabolism. As always,.a carefully designed mix of approaches is likely to yield optimal results in the shortest time and at the lowest cost. Metabolism Studies for Protein Products 10 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 studies are required. Tissue distribution information may be 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 15 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 20 toxicological coverage. If you wish to design a pharmacokinetic study, please proceed to the absorption form. 25 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 30 metabolite structures can both assist in metabolite identification during analytical method development studies and flag putative metabolites as toxicological agents. Go to Metabolic Prediction form In vitro metabolism studies identify the major metabolic pathways that affect the development candidate and its metabolites, and explore the effects of the development 35 candidate on the metabolism (rate) of other drugs and the effect of other drugs on its metabolism. The most comprehensive model for hepatic metabolism are intact liver systems (hepatocytes and liver slices), in which the cofactors are self-sufficient and the natural orientation for coupled phase I/phase II enzymes are preserved. Alternatively, liver microsomes/S9 subcellular fractions offer a convenient way to study a compounds metabolic 40 profile, examine potential drug-drug interactions, and compare species-specific metabolic rates. Finally, the advent of high-throughput recombinant CYP450 systems are used during lead optimization/SAR studies to rapidly identify specific cytochrome P450 substrates and inhibitors. Some of these systems also express cofactors (e.g., NADPH) and are also self-sufficient.

WO 01/57760 PCT/USO1/03011 31 At the screening and optimization stages, 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. 5 Phase I IND Requirements Metabolism information in a Phase I IND usually includes metabolic stability in toxicology species (including single-dose pharmacokinetic studies), identification of main metabolites (as Ml, M2, and not necessarily identified and characterized), identification of metabolizing 10 cytochrome P450s, and induction/inhibition information. However, if the intended first clinical study will enroll patients who could be taking multiple medication (e.g., AIDs or cancer patients), detailed metabolic profiling and drug-drug interaction studies should be conducted to ensure safe use of the compound in the clinic. In those instances where the metabolic pathway of one drug is sufficiently different from that of another, the Sponsor may 15 be able to rationalize not conducting combination toxicology studies. Go to In Vitro Metabolism Form Enzyme inhibition studies assess the potential of a compound to inhibit cytochrome P450 enzymes responsible for the metabolism of other drugs. These studies can be conducted using microsomes and S9 fractions and known substrates of various cytochrome P450 enzymes. 20 The data derived from such studies include IC5 50 and approximate K;. The K; can then be compared to the anticipated (or known) therapeutic blood levels to determine if there is indeed a potential for drug-drug interactions. Enzyme induction studies also provide information about the drug-drug interaction 25 potential of your compound. Induction studies 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 studies by extracting and testing the livers of treated animals. Assays such as effect on duration of phenobarbitone-induced sleep, and 30 zoxazolamine-induced loss of righting reflex in the Primary Pharmacology section offer information regarding enzyme induction. Note that one can also assess potential drug-drug interactions using in vitro assays that involve co- incubation ofthe two study drugs with microsomes, S9 fractions, or recombinant 35 cytochrome P450 isozymes. Inhibition/induction and in vitro drug-drug interaction studies aid the Phase I drug-drug interaction studies considerably. Go to Drug-Drug Interaction Form In vivo metabolism studies are conducted following intravenous and, if applicable, oral (or other) routes of administration and are termed pharmacokinetic studies. These studies yield 40 information regarding absorption and bioavailability (for non-iv administrations), half-life, WO 01/57760 PCT/USO1/03011 32 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 5 pharmacokinetic study, please go to the absorption form which captures information regarding single- and repeat-dose pharmacokinetic studies. For a list of drugs that induce, inhibit, or are substrates for a specific cytochrome P450 isozyme, click on the isozyme of interest: 10 CYPIA2 CYP2C8 CYP2D6 CYP2A6 CYP2C9 CYP2EI CYP2B6 CYP2CI9 CYP3A4 15 Table 6 Your session ID is test 20 and your Session Title is new one Any changes you submit will overwrite this sessions data! In Vitro Metabolism Study 25 Metabolic stability study with: (check all that apply) Human Liver Microsomes/S9 I Hepatocytes J Recombinant human CYP450 0 30 Metabolic identification following incubation with: (check all that apply) Human Liver Microsomes/S9 Hepatocytes ] Recombinant human CYP450 0= 35 Studies to identify metabolizing isozymes with: (check all that apply) Human Liver Microsomes/S9 (look for competition of known substrates) Hepatocytes 40 (look for competition of known substrates) Recombinant human CYP450 Qualitative difference across species with respect to: [Metabolic stability : Metabolic identification 0 WO 01/57760 PCT/USO1/03011 33 Table 6, cont. Identification of metabolites across species and comparison to humans (check all that apply) 5 Mouse |_CD-_ [1i Rabbit Nn ____ [i Rat | None [l Dog | Beagle E Hamster | None _ _ l.. Monkey | None [E guinea pig |None E mini pig I If other please specify . .None ____[Ilj 10 Qualitative differences in metabolic stability across species and comparison to humans (check all that apply) Mouse ~n__ Rabbit ] None _ _ I Rat None _ YDog .None____[.. 15 Hamster Eln | Monkey |NIone __ guinea pig _None l mini pig El If other please specify None _ Qualitative differences across species with respect to metabolic rate 20 and comparison to humans (check all that apply) Mouse None__[Rabbit | N o _ [Rat [ _ _ [ [Dog None __ij Hamster |_on__ [[Monkey N[o None___[ guinea pig None E 3 mini pig IF 25 If other please specify F None il Qualitative differences across species with respect to metabolites and comparison to humans (check all that apply) Mouse None____ Rabbit None 30 Rat Nonene [ ] Dog |o___[lj Hamster _None_ __[Monkey [ one___l guinea pig -None mini pig o If other please specify . None_ _ ___ _E .Send WO 01/57760 PCT/USO1/03011 34 After the metabolism studies were selected, the system generated a Gantt chart, as shown in Fig. 24, that displayed the time that it will take to conduct such studies, the estimated costs, and the amount of non-GMP material required. The user then proceeded to the Toxicology instructional text page, shown below as 5 Text Box 4, to determine what toxicology work needed to be conducted. Text Box 4 10 Toxicology Toxicology is the study 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 15 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 20 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. The following table gives approximate factors for converting doses expressed in terms of 25 mg/kg from one species to an equivalent surface area dose expressed as mg/kg in another species. Mouse Rat Monkey Dog Man To _ 20g 150g 3.5kg 8kg 60 kg 30 From Mouse 1 % 1/4 1/6 1/12 Rat 2 [1[ %[1/4 1/7 Monkey 4 ] 2 1 1 3/5 1/3 Dog 64 5/3 12 35 [ Man | 12 7 3 | 2 | I The types and numbers of toxicology studies required are dependent upon the intended clinical indication, the study population, and intended duration of clinical study, (please complete the Intended Clinical Program form if you have not done so already so that FIRST 40 PASSTM can identify any potential conflicts between the preclinical and clinical programs).

WO 01/57760 PCT/USO1/03011 35 There are 7 types of toxicology studies but for the typical Phase I IND, the Sponsor will need to concentrate on the acute, subchronic (if the clinical study will involve more than 1 day of dosing), and genotoxicity studies. (For compounds that will be administered topically, ophthalmically, optically, vaginally, or via inhalation, please proceed to the special toxicity 5 section.) Acute/Expanded Acute (support single-dose human study) Subchronic/SubAcute. (typically <90 days) Chronic(>90 days) 10 Carcinogenicity Genotoxicity Reproductive Special Toxicity 15 For some classes or types of compounds, there are specific toxicology studies that should be conducted: Oligonucleotides 20 Oncology products Biological Products To view a table that provides an overview of the toxicology studies necessary for various 25 phases of drug development as well as for submission of an NDA, click here. The best way to ensure a successful IND is to have a pre-IND meeting with the FDA to discuss existing preclinical data, planned preclinical studies, and intended clinical program. 30 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. The user submitted to the system dose-range finding studies (non-GLP) and formal GLP acute studies in the CD 35 1 rat and beagle dog. 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 study were known. The 40 user decided to wait until the entire study was completed.

WO 01/57760 PCT/USO1/03011 36 Text Box 5 Acute Toxicity Studies 5 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. Acute toxicity studies in animals are necessary for any pharmaceutical intended for human use. In addition, acute toxicology studies should be conducted for any impurities that are 10 present at >= 0.1%. The information obtained from these studies is useful in choosing doses for repeat-dose studies, 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 15 compounds, please go to Toxicology Studies for Biological Products. Acute toxicity studies in animals should be conducted using two routes of drug administration: 20 1) the route intended for human administration and 2) intravenous administration (100% bioavailability). (Note: if the intended route in humans is intravenous, only IV studies are needed.) Studies done to support an intended clinical study should be conducted in at least two 25 mammalian species, including a non-rodent species, and conducted under GLP. Dose-ranging studies (not GLP) are carried out to determine the doses that should be tested in the pivotal GLP studies. Usually, acute toxicity can be assessed using 3-5 rodents per sex per group and by including vehicle control groups. An observation (or recovery) period of 14 days is usually sufficient. Data collected should include: mortalities, clinical signs 30 (including, time of onset, duration, and reversibility) gross necropsy, findings (including those of, sacrificed moribund, found dead, or terminated at 14 days), clinical pathology, and toxicokinetics. Acute toxicity studies may yield the following information: 35 - the most sensitive species (definition) - a toxicologically relevant species (definition) - a no-effect level (NOEL) and yield a safety margin relative to the proposed clinical dose 40 - relationship of toxicity findings to drug levels in the blood - a target organ of toxicity,(If not, should consider increasing the dose; if you reach doses above 5g/kg without demonstrating toxicity and you have hundred- to thousand-fold safety margin, you should be ok). - a maximum tolerable dose (MTD) (definition) 45 - a maximum non-lethal dose (MNLD) (definition) - reversible and non-reversible toxicities (definition) WO 01/57760 PCT/USO1/03011 37 If there are differences in toxicities across studies (with the same species and strain), the Sponsor will need to explain such differences. Some common reasons for differences in toxicity findings: 5 a) different vehicles which in turn affect plasma levels of drugs or which are toxic on their own b) different batches of drug which have different amounts of impurities c) change in manufacturing process such that more active compound 10 Expanded Acute Toxicity Study In August 1996, FDA published new guidance (61 FR 43934) that describes how single-dose animal studies can support single-dose human clinical trials (i.e., no subacute studies are required). (Note that this guidance was originally intended to be published as part of 15 proposed ICH document but it was published only in the Code of Federal Regulations and, thus, represents the FDA position only.) If acute toxicity studies in animals are to provide the primary safety data supporting single dose safety/kinetic studies in humans (e.g., a study screening multiple analogs to aid in the 20 selection of a lead compound for clinical development), the toxicity studies should be designed to assess dose- response relationships (and thus, would include doses lower than typicallyused in acute studies) and pharmacokinetics. Clinical pathology and histopathology (not routinely done for acute toxicology studies) should be monitored at an early time and at termination (i.e., for maximum effect and recovery). 25 In addition, the following tests should also be conducted and submitted in the IND: 1) Two genotoxicity studies (one study to investigate potential mutagenic effects and another to investigate potential clastogenic effects) 30 2) In vitro receptor screening study 3) In vivo safety pharmacology studies the selection of which can be based on in vitro receptor screening results and knowledge of the mechanism of action of the drug) 4) ADME (but less than what is typically in an IND; depends upon intended clinical use and population to be enrolled in clinical study) 35 Go to Acute Toxicity Form WO 01/57760 PCT/USO1/03011 38 Table 7 Acute Toxicity Studies 5 Dose-range finding studies (non-GLP GLP Studies Rodent Study (select strain if Known) 10 Mouse CD i ] 11Hamster None Rat iNone ___ _ __ _ ij .I___......_.. If other please specify . Routes (check all that apply) Oral IV 19 ip 15 Inhalation [ id sc O If other please specify = 1 I Note: If you need otic, ophthalmic or topical toxicity studies please select iv, above and proceed to Special Toxicity Studies. If intended clinical route is iv or vascular irritation studies, Special Toxicity Studies need to be done. 20 Duration of Treatments Single doses/24 hours__ _ _ 25 Standard Assessments Rodent Study (check all that apply) Clinical Pathology body weight 1 Gross necropsy 0 clinical signs/mortality D food/water consumption 0 toxicokinetics 0 organ weights [ 30 Additional Assessments Options CSF Levels [ All Males Urine Output/electrolytes I] Oj i[ All Females El [ECG ][E Juvenile Animals ] histopathology ] Elderly Animals ] 35 ophthalmologic exams O __ _ _ _ _] Recovery time different than 14 days E WO 01/57760 39 PCT/USO1/03011 Non-Rodent Study (select strain if known) Rait EmNoneMonkey |N e | ~Dog | Beagle_ [ If other please specify 5 Routes (check all that apply) Oral 0 IV Oi Inhalation f7 id I sc D If other please specify . .. Note: If you need otic, ophthalmic or topical toxicity studies please select iv 10 above and proceed to Special Toxicity Studies. If intended clinical route is iv or vascular irritation studies, Special Toxicity Studies will need to be done. Duration of Treatments 15 ingle doses/24 hours .____ Standard Assessments Rodent Study (check all that apply) Clinical Pathology 0 body weight 0 Gross necropsy 0 clinical signs/mortality 0 20 food/water consumption 0 toxicokinetics 0 organ weights Fo__ Additional Assessments Options CSF Levels El All Males 1 I Urine Output/electrolytes LI All Females 25 ECG E Juvenile Animals [ histopathology D Elderly Animals ophthalmologic exams El ____________ Recovery time different than 14 days 2 Estimate highest dose to be used .. 1000 _ _ _ j mg/kg 30 When would you like to _ _-8_weeks_ _ _ start the non- After rodent studies (~8 weeks________) . rodent studies? 35 Additional Comments for Acute Toxicity 40 Se WO 01/57760 PCT/USO1/03011 40 After submitting the acute toxicology study information, the system displayed an updated Gantt chart, as shown in Fig. 25, and all relevant information. 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. 5 Text Box 6 10 The table below presents the high dose anticipated in your clinical study and the highest doses that will be used in the supporting toxicology studies 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. However, to effectively argue safety in the regulatory submission (especially for a non-lifethreatening indication), the Sponsor should state the no effect levels (NOELS) 15 determined in the toxicology studies and determine the safety margin between these levels and the starting dose in the clinical study. The most conservative way to determine safety margins is via using body surface area (refer to Body Surface Area chart). Given that many anticancer compounds are cytotoxic and given the lifethreatening nature of 20 the disease, safety margins for (toxic) oncology products are typically very different than those for non- lifethreatening diseases. The starting dose in a Phase I dose-escalation study is either 1/10th of that dose that cause sever, but reversible, toxicity in 1/10th of the rodents (on a mg/m2 basis) or, if the toxicities were not reversible in the rodent, 1/6th of the highest dose that did not cause severe toxicity in the non-rodent 25 Blood levels (e.g., AUC and the Cmax) 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. 30 Highest High dose High dose High dose Safety Margin anticipated from acute from from (based on high doses) clinical toxicology subacute chronic dose studies toxicology toxicology Acute Subacute Chronic 35 (mg/kg) (mg/kg) studies studies (mg/kg) (mg/kg) 0.1429 1000 N/A N/A 6997.9 N/A N/A WO 01/57760 PCT/USO1/03011 41 The user then proceeded to the subchronic/subacute instructional text page, as shown in Text Box 7, because the intended clinical study was going to be 1-7 days and reviewed the information. 5 Text Box 7 Subehronic-/Subacute (duration <90 days) 10 "Subacute" and subchronic toxicity" are interchangeable terms referring to an experiment in which a drug is administered for a limited period usually 2-4 weeks up to 90 days. A study of this type may serve one or more purposes: It may be a range-finding pilot study to delineate dose and main toxic effects to be considered in the design of subsequent chronic studies (and, thus, is typically not done under 15 GLPS). It may represent a definitive toxicity experiment for a drug that will be administered to man once or only over a very limited period of time, say 2-4 weeks. Examples of "one-shot" medications are: diagnostic compounds; single-dose vermifuges or narcotic antagonists. Compounds used in such a way that no appreciable absorption may occur, as in 20 dermal preparations, may also require only short term animal tests. Note that European applications (whether a CTA or ERC-approved program) would require two-week toxicity studies in two species to conduct a single-dose study in humans. Subchronic studies maybe aimed at selection of the best-tolerated compounds from a series of chemically related drugs with similar action or designed to support preliminary 25 short-term clinical trials of drugs intended ultimately for prolonged use in man. Dose-ranging studies (usually non-GLP and done as part of the pivotal toxicology study) are typically conducted to determine the dose to be used in subchronic toxicity studies. 30 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 subjected to ophthalmological examination. Clinical pathology assessments (hematology, clinical 35 chemistry, urinalysis) should be conducted periodically during the study and after the recovery period. (Note that additional animals will need to be added to each dosing level in order to assess toxicokinetics since the multiple blood draws for both clinical pathology and toxicokineties would render the animals anemic, thereby interfering with the clinical pathology results.) Routine tests may be supplemented or deleted as indicated by the known 40 characteristics of the drug under study. At terminal sacrifice, organs and tissues are examined by the pathologist. Microscopic examination may confirm evidence of organ function changes noted while studies were in progress or may reveal changes not reflected by tests performed during the course of the study. In evaluation of the results, the toxicologist must take into consideration a number of factors: 45 WO 01/57760 PCT/USO1/03011 42 - Severity of changes - Incidence of changes - Dose-response relationships - Known pharmacological activity 5 - Diseases commonly seen in the species used in the tests - Control data, historical as well as immediate Subacute toxicity studies should consider and address the following items: 10 * The most sensitive species - A toxicologically relevant species (defined as such via metabolism, pharmacoldnetic profiles or because of similar pharmacology to humans) - A no-effect level (NOEL) and yield a safety margin relative to the proposed clinical dose-this is more important for subehronic studies than for acute studies 15 - Relationship of toxicity findings to drug levels in the blood - A target orgarn of toxicity - A maximum tolerable dose (MTD) - Reversible and non-reversible toxicities 20 2 Go to SubAcute Toxicity Form 25 The user outlined the subacute toxicology studies on the Sub Acute Toxicity Form, as shown in Table 8. The user chose to conduct both dose-range finding studies (non-GLP) and pivotal GLP toxicology studies 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 30 studies after the in-life portion of the rodent study was complete.

WO 01/57760 PCT/USO1/03011 43 Table 8 Subacute Toxicity Studies (typically <90 days) Dose-range finding studies (non-GLP) z GLP Studies 5 Rodent Study (select strain if known) I mouse I dCD- I Ei I

T

-7 . Hamster None NA_ 10 Rat [iNone _ _ _ld NA Other please | A specify Routes (check all that apply) Oral IV ED ip 15 Inhalation iC id JJLI sc l If other please specify Note: If you need otic, ophthalmic or topical toxicity studies please select iv, above and proceed to Special Toxicity Studies. If intended clinical route is iv or vascular irritation studies, Special Toxicity Studies need to be done. 20 Standard Assessments Rodent Study (check all that apply) Clinical Pathology body weight 0 Gross necropsy 0 clinical signs/mortality J 25 food/water consumption 0 toxicokinetics 0 organ weights I histopathology 0 ophthalmologic exams F _ Additional Assessments Options CSF Levels F All Males I 30 Urine Output/electrolytes IE D All Females ECG ILEJI Juvenile Animals J Elderly Animals 10Oi Recovery time different than 14 days D E] WO 01/57760 PCT/USO1/03011 44 Non-Rodent Study (select strain and duration if known) Rabbit ][ INne [~J I NA I) Dog MBeagle . ..

7 d Monkey | None NA 5 Other please NA specify 1 NA . Routes (check all that apply) Oral IV 77 ip OE Inhalation l id I sc El 10 If other please specify L I Note: If you need otic, ophthalmic or topical toxicity studies please select iv, above and proceed to Special Toxicity Studies. If intended clinical route is iv or vascular irritation studies, Special Toxicity Studies need to be done. 15 Standard Assessments Non-Rodent Study (check all that apply) Clinical Pathology f]body weight Gross necropsy 0 clinical signs/mortality 0 food/water consumption 0 toxicokinetics 0 organ weights 0[histopathology 0 20 ophthalmologic exams o Additional Assessments Options CSF Levels [ All Males Ej Urine Output/electrolytes OE All Females J ECG D Juvenile Animals O 25 Elderly Animals J Recovery time different than 14 days ||E Estimate highest dose to be used | 250 mg/kg When would you like to 30 start the non- Afterinlife port f su acut t study days rodent studies? _ 35 Additional Comments for Acute Toxicity |Send WO 01/57760 PCT/USO1/03011 45 After submitting the subacute study information, the user was informed by the system, in the manner shown in Text Box 8, that the selections made in the subacute study were in conflict with the intended clinical program: the clinical trial was going to enroll pediatric patients and juvenile animals should be used in the subacute toxicology studies. The user 5 was given the opportunity to correct either information and chose to use juvenile animals in the toxicology studies. 10 TextBox8 First Pass has determined that the selections made for the Sub-Acute Toxicology study and the Intended Clinical Program study are in conflict. The selections for Elderly. and the pediatric populations from Intended Clinical Program must match the elderly and juvenile 15 animals selections from the Sub-Acute studies. Please make the necessary changes here. This will update the studies concerned. Length of Duration from Sub-acute Tox _7_days 20 Length of Duration from Therapeutic 1 to 7 days . Indication From Sub-Acute Tox From Intended Clinical Program Juvenile Animals I Pediatric population 25 [[Elderly Animals | Elderly (>65 years) | FS-end 30 After submitting that information, the system displayed an updated Gantt chart, as shown in Fig. 26, and the safety margin relating the subacute toxicology study dose to the intended clinical dose was calculated, as shown in Text Box 9. 35 WO 01/57760 PCT/USO1/03011 46 Text Box 9 The table below presents the high dose anticipated in your clinical study and the highest doses that will be used in the supporting toxicoloy studies and calculates safety margins to 5 give you a very rough idea as to how much of a margin you have built in to your program. However, to effectively argue safety in the regulatory submission (especially for a non-lifethreatening indication), 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 study. The most conservative way.todetermine safety 10 margins is via using body surface area (refer to Body Surface Area chart). Given that many anticancer compounds are cytotoxic and given the lifethreatening nature of the disease, safety margins for (toxic) oncology products are typically very different than those for non- lifethreatening diseases. The starting dose in a Phase I dose-escalation study 15 is either 1/10th of that dose that cause sever, but reversible, toxicity in 1/10th of the rodents (on a mg/m2 basis) or, if the toxicities were not reversible in the rodent, 1/6th of the highest dose that did not cause severe toxicity in the non-rodent. Blood levels (e.g., AUC and the Cmax) should be determined from toxicokinetic work and 20 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. 25 Highest High dose High dose High dose Safety Margin anticipated from acute from from (based on high doses) clinical toxicology subacute chronic dose studies toxicology toxicology Acute Subacute Chronic (mg/kg) (mg/kg) studies studies (mg/kg) (mg/kg) j 30 0.1429 1000 250 N/A 6 1749.475 N/A

Claims (21)

1. A system for providing a development program for a bioactive compound comprising: a computer processor for executing computer software; 5 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 generating a development program output based on said input 10 development data.

2. The system of Claim 1, wherein said first computer storage medium stores data regarding information needed to design a development program for submission to a regulatory agency.

3. The system of Claim 1, wherein said regulatory agency is selected from the 15 group consisting of the FDA, USDA, EPA and foreign equivalents thereof.

4. The system of Claim 1, wherein said first computer storage medium stores 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 20 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.

5. The system of Claim 1, wherein said first computer storage medium comprises a database comprising one or more tables selected from the group consisting of a materials 25 quantity table, a conflicts table, a financial table and a temporal table.

6. The system of Claim 1, wherein said software for prompting user input of development data prompts 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, 30 evaluating primary pharmacology, evaluating ADME, selecting safety pharmacology studies, evaluating toxicology, literature evaluation and patent evaluation. WO 01/57760 PCT/USO1/03011 48

7. The system of Claim 6, wherein said development data inputted by said user for evaluating chemistry of said bioactive compound is selected from the group consisting of the physical properties, the structural confirmation, the method of synthesis, the availability and stable isotopic and radioisotopic labeled availability of said bioactive 5 compound.

8. The system of Claim 6, wherein said development data inputted by said user for evaluating literature and patents is selected from the group consisting of identifying previous clinical studies, identifying known patent publications, identifying known literature publications and identifying known computational information. 10 9. The system of Claim 6, wherein said development data inputted by said user for optimizing the biological properties of said bioactive compound is selected from the group consisting of defining the absorption, metabolism, toxicity and distribution studies to be performed.

10. The system of Claim 6, wherein said development data inputted by said user 15 for defining the intended preclinical program is selected from the group consisting of the class of bioactive compound, the indication, the anticipated dose, the duration of treatment and the study population.

11. The system of Claim 6, wherein said development data inputted by said user for evaluating ADME is selected from the group consisting of defining absorption studies, 20 defining distribution studies, defining metabolism studies and defining excretion studies.

12. The system of Claim 6, wherein said development data inputted by said user for evaluating toxicology is selected from the group consisting of defining acute toxicity studies, defining single-dose toxicity studies, defining repeat dose toxicity studies, defining carcinogenicity studies, defining gentoxicity studies, defining reproductive toxicology studies 25 and defining special toxicity studies.

13. The system of Claim 1, wherein said software for prompting user input of development data operates one or more forms substantially as illustrated in Figs. 4 through

21. 14. The system of Claim 1, wherein said software for processing user input 30 development data processes said data using information selected from the group consisting of data entered by said user on one or more development forms, one or more tables from said WO 01/57760 PCT/USO1/03011 49 first computer storage medium and safety margin calculation information from said first computer storage medium to produce processed user input development data. 15. The system of Claim 14, wherein said tables are selected from the group consisting of a materials quantity database, a financial database and a temporal database. 5 16. The system of Claim 1, wherein said development program output comprises an output selected from the group consisting of time, cost, quantity of materials, conflicts and safety margin values. 17. The system of Claim 1, wherein said development program output is in the format as illustrated as in Fig. 23. 10 18. The system of Claim 1, wherein said system further comprises software for providing user access to said system. 19. The system of Claim 18, wherein software for providing user access to said system is secure. 20. The system of Claim 1, wherein said system further comprises software for 15 identification of a user session as a new session or a past session. 21. The system of Claim 1, wherein said system further comprises software for accessing the Internet.

22. The system of Claim 21, wherein said software for accessing the Internet comprises links to an Internet site selected from the group consisting of MedLine, Toxline, 20 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 and http://ntp server.niehs.nih.gov.

23. The system of Claim 1, wherein said system further comprises a second computer storage medium that comprises one or more databases selected from the group 25 consisting of a literature database, a clinical database and a structural database.

24. The system of Claim 1, wherein said system further comprises software for production of identification session forms.

25. The system of Claim 1, wherein said system is iterative.

26. A system for providing a development program for a bioactive compound for 30 submission to a regulatory agency, comprising: a computer processor for executing computer software; WO 01/57760 PCT/USO1/03011 50 a first computer storage medium coupled to said computer processor for storing computer software and data, wherein said 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; 5 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 primarypharmacology, evaluating ADME, selecting safety pharmacology studies, evaluating toxicology, literature evaluation and patent evaluation; 10 software for processing said user input development data; and software for generating a development program output based on said input development data, wherein said development program output comprises an output selected from the group consisting of time, cost, quantity of materials, and conflicts; wherein said software for prompting, processing and generating is iterative. 15 27. A computer-implemented method for providing a development program for a bioactive compound, comprising: prompting a user to input development data; processing said user input development data; and generating a development program output based on said input development data. 20 28. The method of Claim 27, wherein said method comprises storing 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 25 options; the materials needed to complete various development program options; or potential conflicts during completion of various development program options.

29. The method of Claim 27, wherein said method comprises providing 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. 30 30. The method of Claim 27, wherein said step of prompting comprises prompting user input of development data for a purpose selected from the group consisting of evaluating the chemistry of said bioactive compound, optimizing the chemical properties of said WO 01/57760 PCT/USO1/03011 51 bioactive compound, defining the intended clinical program, evaluating primary pharmacology, evaluating ADME, selecting safety pharmacology studies, evaluating toxicology, literature evaluation and patent evaluation.

31. The method of Claim 27, wherein said step of processing comprises using 5 information from tables selected from the group consisting of a materials quantity database, a financial database and a temporal database.

32. The method of Claim 27, wherein said development program output comprises an output selected from the group consisting of time, cost, quantity of materials, conflicts and safety margin values. 10 33. The method of Claim 27, wherein after said step of displaying, said steps of prompting, processing and generating are reiterated.