Visualize and Summarize Repeat-Dose Toxicology Study Results • toxSummary

toxSummary is an R Shiny app to visualize and summarize repeat-dose toxicology study results. toxSummary app wrapped in R package (which is also called toxSummary) so app can be distributed easily.

Overview

Prior to initiation of clinical trials, repeat-dose toxicology studies are conducted in multiple species to support the safety of the active pharmaceutical ingredient (API) in the proposed clinical dosing regimen, route of administration, and duration of treatment. The primary metric used to extrapolate the safety of clinical dosage from repeat-dose toxicology study results is the safety margin, i.e. the ratio of no observable adverse effect level (NOAEL) from the toxicology study to the proposed clinical dose. This ratio can be calculated by using allometric scaling to approximate the equivalent human dose from that used in the toxicology study based on the body surface area of the species employed or by comparing the empirically measured maximum plasma concentration (Cmax) or total plasma exposure (AUC) between the toxicokinetic animal data and the human pharmacokinetic data, if available. Another important consideration in drug safety evaluation is the nature and severity of the toxicities observed at doses above the NOAEL. As toxicity studies of various durations are typically conducted in multiple species and potentially via multiple routes of administration, it can be challenging to effectively integrate all of this information. In collaboration with the Pharmaceutical Users Software Exchange (PHUSE) Nonclinical Scripts Working Group and with consultation from toxicologists at FDA, an open source R shiny application was developed to allow users to interactively visualize safety margins and the severity of user-defined significant toxicities across studies throughout a drug development program in a single plot. The application can also present this information in tabular form that can be exported in various formats, e.g. CSV, Excel or Word files. These functionalities are designed to facilitate holistic evaluation of the drug safety by generating graphical and tabular summaries of the full toxicological profile of an API.

Installation

Package can be installed from CRAN.

#install toxSummary package
install.packages("toxSummary")

Development version can be installed from GitHub.

# install devtools if already not installed 
install.packages("devtools")

#install toxSummary package
devtools::install_github('phuse-org/toxSummary')

Run the app

library(toxSummary)
toxSummary::toxSummary_app()

Run the app with database connection

library(toxSummary)
toxSummary::toxSummary_app(
    database_path = "path/of/your/database.db",
    studyid_file = "path/for/program_studyid_mapping.csv",
    save_file_path = NULL
)

When save_file_path set to NULL, files will be saved in current working directory. an example database can be found in GitHub repository database link

database_path = "path/of/your/database.db"
studyid_file = "path/for/program_studyid_mapping.csv"
Package does not contain database. Database is too big for a package.

How to run the app from cloned repo.

Clone the GitHub repo and set repo as working directory. If you don’t have any database to connect and want to run app, only run this following code in R console.

pkgload::load_all(".")
toxSummary::toxSummary_app()

To run the app with database connection follow this direction; set repo as working directory and open app.R file (or copy code given below) and run the code. if you connect to your database then change the path to your files. otherwise this will connect to example database available in test_data directory.

pkgload::load_all(".")
db_path <- "test_data/test_db.db"
study_list_path <- "test_data/IND_with_studies_2.csv"
toxSummary::toxSummary_app(
    database_path = db_path,
    studyid_file = study_list_path,
    save_file_path = NULL
)

This will open toxSummary app. The default/example database (in “test_data/test_db.db” directory) only contain few studies.

How to deploy the app

From the installed package

First create app.R file in the working directory.
Then copy the code from here and change the database and file paths.

 toxSummary::toxSummary_app(
    database_path = "path/of/your/database.db",
    studyid_file = "path/for/program_studyid_mapping.csv",
    save_file_path = NULL,
    where_to_run = "rsconnect")

Deploying Shiny app as package is little different. There is no publish button when you open app.R file in RStudio. Running rsconnect::writeManifest() command in R console will create manifest.json file. app then can be deployed on rsconnect running
rsconnect::deployApp() command in R console.

Keep in mind that when app running on server, app need to have access to the files given in database_path and studyid_file argument.

Demo App

A demo app can be found here demo app link