Introduction
If you have submitted an initial marketing application in the US over the past few years, you may have included a BIMO data package along with your clinical information. We at WAYS can attest that in your first endeavor, it can be difficult to understand exactly how this package fits in to the application. Our hope is that this blog can give simple straightforward answers as to why we submit BIMO, what needs to be included, and how it should be presented.
Background
The Bioresearch Monitoring (BIMO) Program was established in 1977, after a survey of the conduct in clinical studies established a need for FDA to be given the right to audit clinical research sites. The intent of the program is to protect the rights and safety of trial participants, verify integrity of the data submitted, and confirm that all regulations for clinical trials are being met, including those for ethics committees and informed consent.
To determine which sites to audit, a wealth of information is needed – including subject data, informed consent, and investigator information for each individual site, to name a few. Gathering this data was a very time-consuming task that often led to hiccups and delays in process. Before long, the agency began to call on sponsors to provide review aids for this information to streamline the process and ultimately speed up appraisals.
In 2011, FDA published an initial guidance that spelled out the expectation and formats for the data elements that reviewers need to carry out site selection. Since they have released a more established Draft Guidance and a Technical conformance guide to aid in the creation of the package.
The request for this data will come from the Office of Scientific Investigations (OSI). The data package should include information from all studies that are considered pivotal to support the efficacy and safety claims for your application. It is always a good idea to confirm with your review division exactly which studies should be included and clarify any questions on study inclusion in your pre-NDA meeting.
Requirements
The BIMO data package should be placed in eCTD section 5.3.5.4 under a Study Tagging File (STF) named “BIMO”. There are three main “parts” to the required elements, and sponsors may also elect to submit an overall BIMO Reviewer’s guide. Below is a breakdown of each component.
Part I: Clinical Study-Level Information
All information in this section will be provided in PDF format. It falls into 3 main subcategories:
A) A comprehensive list of all clinical sites that participated in each pivotal study. Appendix 1 of the BIMO Technical Conformance Guide gives the suggested format for this list to follow. There should be a separate table for each pivotal study.
B) If the sponsor has contracted any clinical research activities to external organizations, they must provide a table for each pivotal study that identifies the location of study-related documents, and whether they were generated by the sponsor or the CRO. If document locations have not been finalized by the time of submission, contact information should be provided for individuals who can provide the information request.
C) The Study Protocol, Protocol Amendments, and Annotated Case Report Form for all pivotal studies are also requested. However, since these are typically already submitted as part of the clinical study reports and data packages within Module 5, it is not required to physically submit duplicate content in the BIMO STF in 5.3.5.4. Sponsors can create digital “pointers” in the BIMO STF, or, if they elect to submit an overall reviewer’s guide, simply state where the information can be located and provide hyperlinks.
Part II: Subject-Level Data Line Listings by Clinical Site
Subject Level Data is required for each site of each pivotal study and should include listings for the following categories: consented subjects, treatment assignment, discontinuations, study population, inclusion and exclusion criteria, adverse events, important protocol deviations, efficacy endpoints, concomitant medications, and safety monitoring.
These files are submitted in PDF format, and there are two main ways they can be organized. Option A is to organize by site, and then by listing. Option B is to organize by site, then subject, then listing.
The figure below illustrates the two options. Proper bookmarking is critical for BIMO listing files and should reflect the flow of the document. Sponsors should aim to submit 1 PDF for Part II per each pivotal study. However, in WAYS’ experience, BIMO listings can be very large, so it is important to be mindful of the 400MB size limit for PDFs per the US validation criteria and determine if there is a need to separate into multiple files.
Source: BIMO Technical Conformance Guide
Part III: Summary-Level Clinical Site Dataset
Sponsors need to provide a single file that contains summary level clinical site data for all sites for all pivotal studies. The file will be in SAS Transport File Format and be named clinsite.xpt. There are 40 variables that should be defined for each study site within the dataset, ranging from administrative information to specific safety and efficacy findings. Appendix 3 of the BIMO Technical Conformance guide defines each variable and how it should be presented.
Whenever datasets are submitted, there should be a Data Definitions table submitted with them. This file serves as a “dictionary” to the reviewer and gives them clarity on the origin of the variables contained within the dataset. This should be provided in .xml format.
Optional: BIMO Data Reviewer’s Guide
While not required, WAYS strongly recommends that sponsors take advantage of the option to submit an overall reviewer’s guide for BIMO. This file can serve as a comprehensive table of contents that provides links to the reviewer so that they can locate all components. It can also serve to provide explanations as to why certain data points may be missing from the clinsite.xpt file (ex. Subjects who transferred sites, dropped out of screening, etc.). This file should be submitted in .pdf format.
Building in eCTD Format
As previously discussed, all BIMO information will go under an STF in Module 5.3.5.4 titled “BIMO”. Files should be given the proper file tags as indicated in the table below:
FDA also prefers that within the file folder structure, there are subfolders for each study, and that Parts I and II are organized within the folders for their individual studies. Since Part III encompasses information for all studies, it should be placed in a “site-level” folder. The reviewer’s guide should be placed in the site level folder. You may need to investigate if your eCTD software is able to create these subfolders. If not, it does not currently cause any major validation issues to not include them.
Source: BIMO Technical Conformance Guide
Conclusion
BIMO data packages contain certain similar elements and are built with a similar structure to data packages that are submitted to support individual studies. However, rather than strictly containing statistical data, they also contain vital administrative information that aids the FDA in choosing clinical study sites to audit. Regular audits ensure that proper practices are followed, which ultimately protects the safety and welfare of clinical trial participants. If you have questions or concerns about the presentation of your BIMO package in your upcoming marketing application, WAYS is happy to help in any way we can.