Module 4.2: Study Reports
The goal of this section is to provide the FDA with all non-clinical reports relevant to the safety and biological activity of your investigational product in the indications of interest. The study reports should be organized in the disciplines outlined in MODULES 4.2.1 through 4.2.3 which mirror Module 2.6 summaries. Please refer to FDA Guidance on the order of reports in this section: The Comprehensive Table of Contents Headings and Hierarchy (fda.gov). It is highly recommended to include a table of contents that showcases the list of all the non-clinical data study reports along with the location for each section. A sample template is provided here.
A snapshot of what a table of contents may look like along with the name of the study reports is provided in the Module 4: Nonclinical study reports and literature references table below. You will note that the studies listed are most likely what you will have for your gene therapy (Refer to discussion on Module 2.6).
Module 4: Nonclinical study reports and literature references
Section | Contents |
|---|---|
4.2.1 | Pharmacology |
4.2.1.1 | Primary Pharmacodynamics |
Construct/delivery optimization in in-vitro and in-vivo, Platform biodistribution (optional) | |
POC/DRF Efficacy and Safety in wild-type mice | |
POC/DRF Efficacy and Safety in wild-type NHPs | |
POC/DRF Efficacy and Safety in Disease Model if needed | |
4.2.1.2 | Secondary Pharmacodynamics |
4.2.1.3 | Safety Pharmacology |
4.2.2 | Pharmacokinetics-biodistribution (reference to Primary PD&Tox) |
4.2.2.1 | Analytical Methods and Qualification/Validation Reports |
Method Validation Report for DNA Biodistribution in mice | |
Bioanalytical Procedure for DNA Biodistribution in mice | |
Method Qualification Report for DNA Biodistribution in Cyno Monkeys | |
Bioanalytical Procedure for DNA Distribution in Cyno Monkeys | |
Method Validation Report for mRNA Biodistribution in mice | |
Bioanalytical Procedure for mRNA Biodistribution in mice | |
Method Qualification Report for mRNA Biodistribution in Cyno Monkeys | |
Bioanalytical Procedure for mRNA Biodistribution in Cyno Monkeys | |
Method Validation Report for protein detection in mice | |
Bioanalytical Procedure for protein detection in mice | |
Method Qualification Report for protein detection in Cyno Monkeys | |
Bioanalytical Procedure for protein detection in Cyno Monkeys | |
Dose Formulation Analysis Validation Report | |
Etc. | |
4.2.2.2 | Absorption (do not complete – not appliable to gene therapies) |
4.2.2.4 | Metabolism (do not complete – not applicable to gene therapies) |
4.2.3 | Toxicology |
Single-dose Toxicity | |
GLP Tox in wt mice | |
Literature References Cited in the Non-clinical Summary |
Some sponsors submit their non-clinical studies on the investigational product for publication in peer-reviewed journals. A copy of the published study may be included as a report in Module 4.
For non-clinical safety studies completed on or after December 17th, 2016, the FDA requires Standard for Exchange of Nonclinical Data (SEND) data to be included with the IND. SEND was developed by the Clinical Data Interchange Standards Consortium (CDISC) to provide a standard format for the submission of non-clinical data, which facilitates the review and analysis of data by regulatory agencies. SEND data should be provided in Module 4 and prepared per electronic data technical requirements (see https://www.fda.gov/industry/fda-data-standards-advisory-board/study-data-standards-resources#Catalog). Most CROs conducting non-clinical studies automatically generate data in SEND format – be sure to ask for it! [1]
Module 4.2.1: Pharmacology
Include a table of contents of the study reports included in this section. Note that these reports are summarized in Module 2.4: Non-clinical overview and Module 2.6.2 and 2.6.3: Non-clinical written and tabulated summaries. (Refer to Module 2.6).
Module 4.2.2: Pharmacokinetics
Include a table of contents of the study reports included in this section. Note that these reports are summarized in Module 2.4: Non-clinical overview and Module 2.6.4 and 2.6.5: Non-clinical written and tabulated summaries. (Refer to Module 2.6).
Module 4.2.3: Toxicology
Include a table of contents of the study reports included in this section. Note that these reports are summarized in Module 2.4: Non-clinical overview and Module 2.6.6 and 2.6.7: Non-clinical written and tabulated summaries. (Refer to Module 2.6).
Module 4.3: Literature
In this section, you must include all the publications cited either in your non-clinical study reports or in the Module 2: Non-clinical section discussions. Any referenced literature needs to include their full copies in this section.