Key FDA Initiatives: From Clinical Trial Modernization to AI Integration

In this edition of regulatory updates, we explore how the FDA is modernizing clinical trials, addressing drug shortages, and leveraging artificial intelligence for better healthcare outcomes. We also cover recent congressional updates, data integrity guidance, and the new Platform Technology Designation programs, which shed light on the implications and advancements in the regulatory landscape.

FDA update to Congress

On May 22nd, the House Energy and Commerce Health Subcommittee convened a hearing with all three directors of the FDA's human medical product centers: Patrizia Cavazzoni (CDER), Peter Marks (CBER), and Jeff Shuren (CDRH). The directors provided updates on the implementation of FDORA and the latest user fee reauthorizations and addressed various topics raised by committee members.

Clinical Trial Modernization, RWD, and Diversity

The FDA has implemented several key strategies to modernize clinical trials, with a strong emphasis on embracing technological advancements and promoting inclusivity.

CDER Center for Clinical Trial Innovation (C3TI): Launched by the FDA in, the C3TI serves as a central hub within the Center for Drug Evaluation and Research (CDER) to champion innovative approaches to clinical trial design and execution. By fostering enhanced communication and collaboration, C3TI aims to improve drug development efficiency, ultimately bringing patients safe and effective treatments faster.

Decentralized Clinical Trials (DCTs) and Digital Health Technologies (DHTs): The FDA acknowledges the transformative potential of DCTs, which leverage locations beyond traditional clinical trial sites, and DHTs, which streamline data capture directly from individuals. Recognizing that these technologies can reduce participation barriers and enhance diversity, the FDA has issued draft guidance on implementing DCTs and actively develops resources to support their use. Examples include the FDA DHT for Drug Development website and increased stakeholder engagement opportunities.

Promoting Diversity and Inclusion: Acknowledging the importance of representative participant populations, the FDA actively promotes diversity and inclusion in clinical trials through guidance documents and policy initiatives. Key efforts include draft guidance on Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials and a draft guidance on the Collection of Race and Ethnicity Data in Clinical Trials and Clinical Studies for FDA-Regulated Medical Products. The agency emphasizes the use of standard terminologies for race and ethnicity to ensure consistency in data collection and reporting.

Enhancing Efficiency and Reducing Timelines: Recognizing the need for expedited drug development, the FDA has taken steps to streamline its processes, including those related to clinical trials. For instance, CDRH has significantly reduced the median time for clinical trial authorization and established new policies for early feasibility studies. These initiatives aim to make clinical trials more efficient without compromising safety and effectiveness.

In addition to these core modernization efforts, the FDA is exploring other innovative approaches, such as the use of Real-World Data (RWD) and Artificial Intelligence (AI) in clinical trials.

Drug Shortages, Medical Product Supply Chain, and LDTs

Drug and medical device shortages remain a major concern. Rep. Frank Pallone Jr. asked the FDA to comment on legislation that would mandate notifications about potential shortage-causing demand spikes and improve API supply chain transparency. Dr. Cavazzoni agreed, noting that such tools could help the FDA prevent and address drug shortages.

The FDA's recently finalized rule on laboratory-developed tests (LDTs) was also a hot topic of discussion, with members questioning the FDA's resources to implement it. Dr. Shuren defended the rule, stating that its phased enforcement would allow the agency to integrate LDT manufacturers into user fee negotiations to secure necessary resources.

The FDA’s final rule on LDTs made a small but significant change to its regulations by explicitly stating that IVDs are “devices” under the FDCA, even when made by a laboratory. The final rule also established a five-stage, four-year phaseout policy to apply the same regulatory requirements for IVDs to LDTs.

The FDA’s final rule on LDTs has not meaningfully modified the phaseout timeline from the proposed rule despite receiving more than 6,500 comments. However, the final rule significantly modifies what categories of LDTs are subject to full or partial enforcement discretion.

The FDA’s final rule on LDTs, which will begin to be implemented in a matter of weeks, is currently facing pushback from members of Congress who believe that the VALID Act offers more tools and flexibility for regulating in vitro diagnostics.

Artificial Intelligence

Committee members raised questions about the FDA's use and regulation of AI. The panelists highlighted their collaborative work outlined in a recent white paper, detailing how CDER, CBER, and CDRH will regulate AI collectively. While acknowledging the FDA's expertise in data science for reviewing AI-related applications, Dr. Cavazzoni noted that infrastructure improvements, such as better computing capabilities for algorithm review, are needed. Dr. Shuren added that the current medical device framework might be ill-equipped for increasingly sophisticated generative AI technology, advocating for a post-market monitoring model with third-party certification

Data Integrity Guidance

On June 3rd, 2024, the FDA finished collecting comments on its draft guidance that addresses data integrity issues in bioavailability (BA) and bioequivalence (BE) studies. The guidance provides recommendations to applicants and testing sites on achieving and maintaining data integrity for studies submitted to the Center for Drug Evaluation and Research (CDER). The guidance covers BA and BE study data submitted in support of investigational new drug applications (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologic license applications (BLAs). The guidance also addresses the bioanalytical portions of clinical pharmacologic studies supporting CDER-regulated BLAs.

Here is a high-level overview of the topic:

Data Integrity: A Framework

The FDA defines data integrity as “the accuracy, completeness, and reliability of data.” To manage and document data to ensure these qualities, the FDA recommends using the “ALCOA” principles as a framework (attributable, legible, contemporaneous, original, and accurate).?

The FDA emphasizes the importance of a quality culture within organizations that conduct BA and BE studies. According to the FDA, a strong quality culture, where data integrity is treated as a core value, is essential to preventing errors and misconduct.

Actions Study Sponsors Can Take to Ensure Data Integrity

To ensure data integrity, the FDA recommends that study sponsors take the following actions:

Vendor Qualification: Only use qualified testing sites, taking into account the education, training, and experience of the site’s personnel. Sponsors should also look for sites with adequate quality management systems in place.

Monitoring: Develop and follow a monitoring plan that is independent of the testing site’s own quality assurance monitoring. The monitoring plan should cover the entire dataflow of the study.

Auditing: Audit testing sites to confirm compliance with monitoring plans. Audits should assess whether sites are performing activities according to protocols and regulatory requirements and whether data integrity is maintained throughout the data lifecycle.

Actions Testing Sites Can Take to Ensure Data Integrity

Testing sites can take the following steps to ensure data integrity:

Organizational Structure: Create a site organizational structure that ensures BA/BE studies are conducted and analyzed according to regulatory requirements.

Personnel: Ensure personnel are adequately trained and qualified and that sites have adequate resources to meet their responsibilities. Clearly define roles, responsibilities, authority, and interrelation of personnel.

Data Integrity Policies: Establish data integrity policies and objectives that are understood, implemented, and maintained throughout the organization.

Quality Culture: Create and encourage a culture of quality.

Quality Management System: Implement a quality management system that is reviewed periodically to ensure it is effective.

The FDA states that establishing a quality culture and implementing a quality management system should be a top priority for testing sites. Testing sites with strong quality cultures are more likely to prevent data integrity problems and more likely to identify potential data integrity risks earlier.

Quality Management System Recommendations

The FDA recommends that quality management systems account for the following:

Data governance: This refers to all of the arrangements in place to ensure data integrity throughout the data lifecycle—collection, generation, recording, modification, processing, maintenance, storage, retrieval, transmission, and disposition.

Records management: All data should be recorded promptly and accurately, with associated metadata. Data should be stored in a way that ensures it is protected, enduring, retrievable, and readable.

Sample analysis: If sample testing is done at a third-party site, specific quality management provisions should be put in place. Methods used for sample analysis should be validated. Audit trails should be maintained and reviewed.

Data storage and backup: Paper-based records should be secured to prevent alteration or loss. Electronic data should be stored on a system with limited access. Backups should be made according to pre-defined procedures.

Archival and retrieval: All data should be archived for at least five years within two weeks of study completion. Controls should be in place to prevent archived data from being damaged, altered, or deleted, and an individual should be responsible for managing data archives.

Training: All personnel should be trained on data integrity, including how to prevent, detect, and report issues. Training should include regulatory requirements.

Access and privileges: Use access controls to limit what personnel can access based on their roles and responsibilities. All personnel should have unique logins and passwords should be updated regularly.

Audit trails: Audit trails should document all changes to BA/BE data. This includes capturing who made the changes, when they were made, and why.

Quality assurance and control: Quality management systems should include quality assurance and quality control programs. A quality assurance program ensures that processes, controls, equipment, and personnel are compliant with applicable data integrity requirements. A quality control program is meant to identify and correct data integrity issues.

Consequences of Data Integrity Issues

The FDA notes an increased risk of data integrity issues arising in BA and BE studies. This increased risk is due to the increasingly complex nature of BA and BE studies, and the increased price sensitivity and competition for conducting these studies.

?According to the FDA, data integrity issues can result in the following consequences:

• Enforcement actions against sponsors and testing sites;
• Requirement to repeat studies;
• Withdrawal of approvals;
• Changes to product bioequivalence ratings;
• FDA refusal to approve new marketing applications.

To protect themselves, the FDA recommends that sponsors and testing sites take immediate steps to ensure data integrity. Sponsors should also ensure that contracts with testing sites define the responsibilities of each party with respect to data integrity, regulatory, and other operational aspects of the development and testing program

Platform Technology Designation program.

The purpose of the FDA's Platform Technology Designation program is to support the development and review of platform technologies incorporated within or utilized by multiple drug or biological products. The FDA recognizes that certain platforms, such as those for mRNA vaccines and CRISPR products, have significant potential. The program is intended to leverage data and information about platform technologies across related products during development. In a newly released Draft Guidance from the FDA entitled Platform Technology Designation Program for Drug Development, the FDA addresses its new designation program for platform technologies, which is intended to bring efficiencies to drug development, manufacturing, and review processes for applications that incorporate designated platform technologies.

Criteria for Designation

• The technology is incorporated in or used by an approved drug or biologic.
• Preliminary evidence demonstrates that the platform technology has the potential to be incorporated into or used by more than one drug or biologic without adversely affecting quality, manufacturing, or safety.
• Data or information indicates that incorporation or use of the platform technology has a reasonable likelihood to bring significant efficiencies to the product development or manufacturing process and to the review process.

Potential Benefits for Sponsors Receiving Platform Technology Designation

• Receiving timely advice and having additional engagement with the FDA during product development, where the FDA may prioritize interactions where platform technology designation can have the most significant public health benefit or impact.
• Leveraging data from prior approved products, such as batch or stability data.
• Leveraging nonclinical safety data to streamline nonclinical work for subsequent products.
• Considering previous FDA inspectional findings for subsequent marketing applications related to the manufacture of a drug or biologic that incorporates or uses the designated platform technology.

The FDA's recent initiatives and guidance have far-reaching implications for biopharma. By prioritizing data integrity, embracing innovative technologies, and addressing critical issues like drug shortages, the FDA sets new standards to enhance patient safety, streamline drug development, and foster greater inclusivity in clinical trials.