As 2023 draws to a close, the FDA has issued several final guidances, including documents on collecting trial data with digital health technologies, developing rare disease drugs and biologics, and using real-world data sources, as well as a new draft guidance on clinical trial master protocols.

Master Protocols for Drug and Biological Product Development

The new draft guidance includes many principles of the FDA’s May 2021 guidance on master protocol trials for COVID-19 treatment and prevention, which expired at the declared end of the public health emergency in May 2023.

The draft expands the application of those principles into other therapeutic areas, offering advice on designing and analyzing clinical trials conducted under master protocols, focusing on randomized umbrella and platform trials across a range of therapeutic areas.

Included are recommendations on randomization, control groups, informed consent, blinding to treatment assignment, adaptive design challenges, multiplicity, comparisons between drugs and safety, in addition to considerations on trial oversight, data-sharing and information dissemination.

An FDA guidance snapshot, a visual tool outlining key guidance content, was also released and can be viewed here.

Comments on the guidance are due by Feb. 22, 2024.

Read the guidance here.

Rare Diseases: Considerations for the Development of Drugs and Biological Products

Some major changes from the February 2019 draft version include:

• New sections (safety considerations, pediatric considerations and participation of patients and patient groups in drug development programs)
• New considerations for nonclinical studies
• Information on using external controls and early randomization
• Information on changes to drug substance and manufacturing processes
• The removal of the natural history section, with reference to a separate March 2019 draft guidance

Read the guidance here.

Digital Health Technologies for Remote Data Acquisition in Clinical Investigations

Clarifying the meaning of digital health technology (DHT) functions, this final guidance, based on the December 2021 draft, provides further explanation of DHT regulatory considerations and now includes references to Form FDA 1571 and Form FDA 356h for tracking submissions that include DHT data as well as:

• Revisions to the section on conducting verification, validation and usability evaluations
• Clarification on protecting and retaining DHT records
• Clarification on sponsor and investigator roles regarding DHTs
• Additional recommendations on managing changes to DHTs during clinical trials, including updates to hardware/software and new models/versions
• Various editorial changes intended to improve clarity

Read the guidance here.

Data Standards for Drug and Biological Product Submissions Containing Real-World Data

With its finalization from the December 2021 draft, the guidance is now clearer on the FDA’s perspective on challenges to using currently supported data standards for real-world data sources.

The document also includes more detail on available FDA resources on the use of data standards for submitted trial data.

Read the guidance here.

Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products

This final guidance has seen considerable changes from its November 2021 draft. For example, sponsors intending to use registry data in their drug and biologic submissions are responsible for making sure the registry’s characteristics support the collection of relevant and reliable data, including when the data are from a registry not managed or designed by the sponsor.

The FDA also expects sponsors to have access to the registry data’s metadata, the guidance notes. Other additions and changes include:

• Statements noting that registry data are sometimes used to evaluate a drug received during routine medical practice, such as for evaluating clinical outcomes in underrepresented populations
• Statements noting that registries should have a plan to reduce missing assessments and minimize the loss to registry participant follow-up
• Additional considerations for linking to other data sources
• Removal of examples of pregnancy-related information that may be gathered by a registry, as this is covered in a separate guidance
• Removal of some terms that may be defined differently by different stakeholders that were not needed to understand the guidance

Read the guidance here.