Establishing Traceability in FDA Reviews through the Use of CDISC Standards, SDRG, and ADRG: A Comprehensive Guide

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Introduction

The United States Food and Drug Administration (FDA) review process is a crucial component of ensuring the safety and efficacy of medical products, including drugs, biologics, and medical devices. During this process, the FDA reviews the data submitted by the applicant to determine whether the product under investigation meets the necessary requirements for approval. A critical aspect of this process is the ability to establish traceability between the data collection stage and the analysis. This traceability is essential for the regulatory review, as any gaps or inconsistencies may compromise the evaluation of a submission.

This comprehensive guide discusses the importance of traceability in the FDA review process and how the use of CDISC (Clinical Data Interchange Standards Consortium) standards, SDRG (Study Data Reviewer’s Guide), and ADRG (Analysis Data Reviewer’s Guide) can improve traceability, thereby enhancing the efficiency and effectiveness of the review.

The Importance of Traceability in the FDA Review Process

Traceability is a fundamental aspect of the FDA review process, as it enables reviewers to follow the data from its source through to the final analysis. This allows reviewers to assess the accuracy, completeness, and consistency of the data, ensuring that the conclusions drawn from the analysis are valid and reliable. If the FDA reviewer is unable to trace the data, the regulatory review of a submission may be compromised, potentially leading to delays or even the rejection of an application.

Improving Traceability with CDISC Standards

The CDISC standards are a set of global, platform-independent data standards that facilitate the acquisition, exchange, submission, and archiving of clinical research data. By using these standards, applicants can improve the traceability of their data, making it easier for FDA reviewers to assess the quality and reliability of the data and the conclusions drawn from it. The CDISC standards include the Study Data Tabulation Model (SDTM), which provides a standardized format for the submission of clinical trial data, and the Analysis Data Model (ADaM), which provides a standardized structure for the analysis of clinical trial data.

The Role of the SDRG in Enhancing Traceability

The SDRG is a key document in the FDA review process, as it describes any special considerations or directions that may facilitate an FDA reviewer’s use of the submitted data and helps the reviewer understand the relationships between the study report and the data. The SDRG establishes the traceability of the SDTM datasets and the raw data, making it easier for the FDA reviewer to follow the data from its source through to the final analysis.

In cases where non-CDISC data is converted to CDISC standard, traceability is often the main issue. The SDRG should describe any special considerations or directions that may facilitate an FDA review and help the reviewer understand the relationships between the study report and the data.

Example of Special Consideration in the SDRG

In some instances, fields in the Case Report Form (CRF) may not be tabulated in the SDTM datasets. These fields are annotated as “Not Submitted” in the CRF. All fields that are annotated as “Not Submitted” must meet the following criteria:

1. Only used to trigger an event or record reported for a subject.
2. Not needed for SDTM or Analysis.
3. Not available in raw data, for site use only.
4. Redundancy. The information was already captured by other variables.
5. Not mapped to SDTM because there were no results.
6. To facilitate certain operational processes, including data cleaning and dynamically creating additional forms in the electronic data capture system.
7. Only used to differentiate admission & discharge elements, for deriving start date & end date.

In cases where fields in the CRF meet the criteria listed above and are annotated as “Not Submitted,” there should be an explanation provided in the SDRG detailing the reasons for the data not being submitted. This clarification will help the FDA reviewer understand the rationale behind the exclusion of certain data points and allow them to assess the impact of these exclusions on the overall analysis.

Structure of the SDRG

The SDRG must be written according to a specific structure to ensure that it effectively communicates the necessary information to the FDA reviewer. The Pharmaceutical Users Software Exchange (PHUSE) provides a template to guide the creation of the SDRG. The various sections of the reviewers’ guide are as follows:

1. Introduction a. Purpose b. Acronyms c. Study Data Standards code lists and Dictionary Inventory
2. Protocol Description a. Protocol Number and Title b. Protocol Design c. Trial Design Datasets

By following this structure, the SDRG will provide a clear and comprehensive overview of the study data and any special considerations that may impact the FDA review process. This will facilitate the reviewer’s understanding of the data and its relationship to the study report.

The Role of the ADRG in Enhancing Traceability

While the SDRG focuses on the traceability of the SDTM datasets and raw data, the ADRG is a separate document that provides FDA reviewers with context for the analysis datasets. The ADRG also provides a summary of ADaM conformance findings, helping to ensure that the analysis datasets adhere to the CDISC ADaM standards. Additionally, the ADRG duplicates information found in other submission documentation, such as the protocol, statistical analysis plan (SAP), clinical study report, and define.xml. By doing so, the ADRG serves as a comprehensive resource for the FDA reviewer, allowing them to quickly reference and verify critical information related to the analysis datasets.

In conclusion, traceability is a crucial component of the FDA review process, as it allows reviewers to assess the accuracy, completeness, and consistency of the data and the conclusions drawn from it. By using CDISC standards and providing clear, well-structured SDRG and ADRG documentation, applicants can improve the traceability of their data, making it easier for FDA reviewers to evaluate the quality and reliability of the data and the conclusions drawn from it. By ensuring that data submissions are transparent and traceable, applicants can enhance the efficiency and effectiveness of the FDA review process, ultimately leading to more rapid and accurate evaluations of the safety and efficacy of medical products.