From Informed Consent to Diagnostics: FDA's Comprehensive Regulatory Reforms

The clinical research landscape is on the cusp of a significant transformation, guided by the FDA's latest initiatives to refine informed consent documents and enhance the overall clarity of participant involvement in trials. At the heart of these changes is a deliberate shift towards a more participant-centric approach, ensuring that individuals can make informed decisions with ease and full understanding. Coupled with this are groundbreaking adjustments in the regulatory oversight of laboratory-developed tests, modernizations in the guidance for Data Monitoring Committees, innovative paths for Alzheimer's therapy development, and a fresh perspective on master protocols for drug development. These developments promise not only to safeguard participant welfare but also to streamline and enrich the process of medical advancement.

Informed Consent

Recent initiatives by the FDA and other regulatory bodies, which were long overdue, aim to enhance the clarity and understanding of informed consent documents for prospective research participants. There is a general shift towards a more participant-centered approach in presenting trial information. The guidance targets to bridge the regulatory requirements between the FDA and the Common Rule, focusing on the necessity of clear, concise, and understandable informed consent processes that respect participant autonomy and decision-making.

This initiative is part of broader efforts to align FDA regulations with the Common Rule, emphasizing a concise and focused presentation of information crucial for informed decision-making by participants.

Innovative formats, such as "bubbles" and bullet points, are encouraged to make the informed consent documents more understandable and engaging.

The guidance highlights several core elements that should be included in the key information section of informed consent documents, such as voluntary participation, study purpose, risks and benefits, alternatives, and compensation for research-related injuries.

This change to ICF requirements truly underscores the need for clinical trial sponsors, investigators, and Institutional Review Boards (IRBs) to revisit and potentially revise their informed consent processes and documents to ensure compliance and enhance participant comprehension.

Lab-derived Tests

FDA is evolving its stance on the regulation of laboratory-developed tests (LDTs), which are in vitro diagnostics (IVDs) that are designed, manufactured, and used within a single laboratory. Historically, these tests have been largely unregulated under the Clinical Laboratory Improvement Amendments (CLIA), which do not assess their analytical or clinical validity.

The FDA is concerned about the lack of validation, safety, and effectiveness of LDTs, which could lead to potential patient harm. The agency's shift towards a more rigorous oversight approach includes proposing a rule to classify LDTs as medical devices, requiring premarket review for higher-risk categories, and implementing new quality standards.

An aptly named the Verifying Accurate Leading-edge IVCT Development (VALID) Act - first introduced in 2018 and then again in 2023 - intended to boost FDA oversight and necessitates approval of certain high-risk LDTs; this act faces opposition from industry groups that posit that VALID duplicates CLIA and CMC requirements. Nonetheless, the FDA has moved forward with a pilot program for oncology LDTs, aiming to establish performance benchmarks for these tests. The key concern is the loss of intellectual property (IP) rights as, under the new rule, LDT performance specs will be publicly available.

Data Monitoring Committees

The FDA has issued a new draft guidance for the use of Data Monitoring Committees (DMCs) in clinical trials, aiming to replace the 2006 guidance. This update acknowledges the evolving role of DMCs in overseeing clinical trials, reflecting their increased utilization in adaptive trial designs, safety reporting, and the global expansion of medical product development.

The guidance suggests broader contexts for DMC involvement, such as in early phase studies and various trial sizes, emphasizing the importance of DMCs in trials involving significant safety concerns and vulnerable populations and in implementing adaptive study designs.

It also addresses the composition of DMCs, recommending diversity in expertise without specifying numbers or types of members as before. The guidance suggests a closer interaction between DMCs and the FDA. It highlights the importance of DMCs in safety monitoring and the practical considerations for their use in short-term trials.

Biomarkers for Alzheimer's

Recently, the FDA updated its draft guidance for the development of Alzheimer's disease therapies, especially focusing on the early stages of the disease before dementia becomes overt. This updated guidance marks a significant shift from the 2018 document by including a new section on surrogate endpoints and the process for accelerated approval.

The FDA now explicitly allows the use of biomarker data, like the brain amyloid beta burden, as surrogate endpoints for accelerated approval under the condition that they are "reasonably likely to predict clinical benefit." However, it mandates post-approval trials to validate clinical efficacy.

This move reflects the FDA's nuanced approach to balancing the urgent need for new Alzheimer's therapies with the necessity of ensuring their efficacy and safety. Additionally, the guidance advises sponsors to include clinical outcome data in their applications for a more comprehensive evaluation, even if seeking accelerated approval.

This updated draft guidance comes on the foothills of the agency's pushback for Eli Lilly's TRAILBLAZER-ALZ 2 study for its investigational antibody donanemab, noting its unique design and the implications for drug approval processes.

Master Protocols

FDA released draft guidance on master protocols for drug and biological product development, aiming to streamline and accelerate the process of drug development. Master protocols, as defined by the FDA, facilitate the assessment of one or more medical products across various diseases or conditions through a structured approach incorporating multiple sub-studies.

Stakeholders, including the Biotechnology Innovation Organization (BIO) and Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard (MRCT), have raised concerns and suggestions regarding the scope, clarity of trial designs, and methodologies like randomization and blinding. The guidance primarily focuses on randomized umbrella and platform trials but has received requests for broader inclusion of trial types and methodologies, such as basket trials and Bayesian trial design.