Guidance Breakdown: FDA Issues 2 Draft Guidances Covering BIMO Inspections
Regulators present new guidelines for planning and conducting BIMO inspections.
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The FDA has issued two draft guidances on bioresearch monitoring (BIMO) inspections.
The first covers information to assist the agency in planning these inspections.
The second covers best practices for communicating to the FDA before, during, or after an inspection.
Both cover sponsors that have submitted new drug applications (NDAs), biologics license applications (BLAs), and supplements.
The BIMO inspection planning guidance
This guidance specifies the format for the electronic submission of BLA and NDA content for the planning and conduct of CBER Bioresearch Monitoring inspections using the eCTD. It should be read in conjunction with the BIMO technical conformance guide issued in August 2022, which covers the specifications for preparing and submitting clinical study information and subject-level data line listings by clinical sites.
The planning guidance states that “reviewers from BMB [CBER’s Bioresearch Monitoring Branch], the Office of Vaccines Research and Review, Office of Therapeutic Products, Office of Blood and Research Review, and the Office of Biostatistics and Pharmacovigilance rely on timely access to accurate data in BLA and NDA submissions to issue inspection assignments as early in the review process as possible.”
The guidance describes where to submit the clinical study-level information, subject-level information by clinical site, and the summary-level clinical site dataset in the electronic Common Technical Document (eCTD).
More specifically:
Clinical study-level information must be submitted in eCTD Module 5 (M5) — Clinical Study Reports. This includes comprehensive tables listing all clinical sites that participated in the studies, tables listing entities contracted for clinical study-related activities, protocols, protocol amendments, and annotated case report forms.
Subject-level data line listings by clinical site should also be included in eCTD Module 5. These listings should include primary data points and derived data for each clinical site that consented subjects, necessary for verifying key study data during inspections.
The summary-level clinical site dataset, named “clinsite” for submission and tracking purposes, is submitted in eCTD Module 5. This dataset should contain data characterizing individual clinical investigator sites, describing aspects of the studies associated with these sites, and presenting characteristics and outcomes at the site level. The dataset includes data from all major studies used to support safety and efficacy in the application.
All these files must be submitted electronically via the FDA Electronic Submission Gateway (ESG) or using appropriate physical media. The Bioresearch Monitoring Technical Conformance Guide, which is periodically updated to reflect current standards and practices, provides more detailed information on the submission process and required formats.
A couple of other critical points from this planning guidance include:
The importance of data integrity: The FDA reiterates that accurate and timely data submission is crucial for planning BIMO inspections. This includes identifying clinical investigator sites and other regulated entities for on-site inspections.
Risk-based site selection: CBER plans to use a risk-based model to select clinical investigator sites for inspection. This model uses risk parameters to identify sites early in the review process, allowing for timely inspections and resolution of significant findings. This approach helps meet PDUFA timeline goals and allows applicants to address inspection observations early in the review cycle. The guidance does not elaborate in detail on the specific risk parameters used in this model; however, the summary-level clinical site dataset, named "clinsite" for submission purposes, is intended to provide critical information that assists in the selection of sites for inspection. This dataset characterizes individual clinical investigator sites, describes aspects of the studies associated with those sites, and presents the characteristics and outcomes of the study at the site level.
Recommendations
We suggest considering a few action items in light of this draft guidance:
Update your submission formats. Make sure all clinical study-level information, subject-level data line listings by clinical site, and summary-level clinical site datasets are prepared in the specified electronic format for eCTD Module 5. Follow the Bioresearch Monitoring Technical Conformance Guide guidelines for the detailed technical specifications and format requirements.
Organize your clinical study data. Create comprehensive tables listing all clinical sites that participated in studies, including accurate contact information. Prepare tables listing all entities to whom clinical study-related activities have been contracted, specifying the responsibilities and activities contracted.
Maintain detailed protocol documentation. Make sure all protocols, protocol amendments, and annotated case report forms for major studies are up-to-date and ready for submission. You should be using a robust document management system (DMS) to store, organize, and track all protocols, amendments, and annotated case report forms. That DMS must have version control and easy retrieval of documents for submission.
Prepare subject-level data listings. Generate by-site subject-level data line listings that include primary data points and derived data for inspection verification. Implement rigorous data quality checks to ensure the integrity of subject-level data line listings. As part of this, provide detailed documentation on the methods and criteria used for generating subject-level data listings to facilitate FDA review. They will be looking for it. Include clear annotations and explanations for any derived data points to support inspection verification.
Compile a summary-level clinical site dataset. Prepare a comprehensive summary-level dataset formatted according to the FDA Data Standards Catalog that includes data from all major studies used to support safety and efficacy claims. Follow the FDA Data Standards Catalog meticulously to format the summary-level clinical site dataset accurately. Include all required data elements and ensure the dataset provides a clear and comprehensive overview of study sites and outcomes.
Also, make sure systems and processes are in place for electronic submissions via the FDA Electronic Submission Gateway (ESG).
The BIMO inspection best practices guidance
The second draft guidance addresses records, information and best practices for communicating with the FDA before or during an inspection. Its issuance complies with a mandate in the Food and Drug Omnibus Reform Act of 2022 (FDORA).