Decentralized Clinical Trials: FDA Guidance and Regulatory Considerations

Decentralized Clinical Trials: FDA Guidance and Regulatory Considerations

Key Takeaways

What Is a Decentralized Clinical Trial

A decentralized clinical trial (DCT) is a clinical trial in which some or all trial-related activities occur at locations other than a traditional clinical trial site. The "decentralized" descriptor refers to the distribution of trial activities across multiple locations, including participants' homes, local healthcare facilities, pharmacies, and virtual platforms.

DCT Spectrum

DCTs exist on a spectrum from fully traditional to fully virtual:

Most DCTs in practice are hybrid models. Fully decentralized trials remain rare, particularly for interventional drug studies where physical assessments or supervised drug administration are required.

DCT Elements

FDA Draft Guidance: December 2023

FDA published the draft guidance "Decentralized Clinical Trials for Drugs, Biological Products, and Devices" in December 2023. This guidance consolidates FDA's position on DCTs and addresses regulatory considerations across the trial lifecycle.

Scope

The guidance applies to clinical investigations regulated under:

• 21 CFR Part 312 (INDs for drugs and biologics)
• 21 CFR Part 812 (IDEs for devices)
• 21 CFR Part 50 (protection of human subjects)
• 21 CFR Part 56 (institutional review boards)

Key Principles

FDA's guidance is built on several core principles:

1. DCTs are not a separate regulatory category. The same regulations that apply to traditional clinical trials apply to DCTs. The guidance provides flexibility in how compliance is achieved, not exemptions from requirements.

2. Participant safety is paramount. Decentralized elements must not compromise participant safety. If a safety assessment requires in-person evaluation, it must occur in person regardless of the DCT design.

3. Data integrity must be maintained. Remote data collection must produce data of equivalent quality to traditional site-based collection. The sponsor must demonstrate that DCT technologies and processes maintain data integrity per 21 CFR Part 11 and applicable guidance.

4. The investigator retains responsibility. The principal investigator (PI) is responsible for the conduct of the trial at the site, including oversight of all trial-related activities, regardless of where those activities occur. Remote elements do not transfer responsibility from the PI.

Remote Informed Consent

Regulatory Framework

Informed consent requirements are governed by 21 CFR Part 50 (Subpart B). The regulations require that consent be obtained "under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate" (21 CFR 50.25).

The regulations do not mandate in-person consent. FDA has clarified that remote consent processes can satisfy 21 CFR Part 50, provided:

eConsent Requirements

FDA's Position on Remote Consent

FDA's December 2023 draft guidance states that sponsors may use electronic methods for informed consent, including:

• eConsent platforms: Interactive digital platforms that present consent information, assess comprehension, and capture electronic signatures
• Video-based consent: Live video call between investigator/study staff and participant during the consent process
• Hybrid consent: Initial consent discussion in person, with subsequent re-consent or amended consent conducted remotely

FDA expects that:

• The eConsent platform's electronic signature functionality complies with 21 CFR Part 11 or applicable regulations
• The consent process includes an opportunity for the participant to ask questions of the investigator or qualified designee
• The IRB reviews and approves the specific eConsent process and platform
• Audit trails capture the consent process in sufficient detail

State-Level Considerations

Informed consent laws vary by state. Some states have specific requirements for:

• Witness signatures (which may need to be in person in some jurisdictions)
• Notarization (rare but exists in some contexts)
• Written vs electronic consent format preferences
• Telehealth consent requirements that may affect telemedicine-based consent

Sponsors must evaluate state-level requirements for each site's jurisdiction and for each participant's location.

Telemedicine in Clinical Trials

Using Telemedicine for Study Visits

FDA's guidance permits telemedicine visits as alternatives to in-person visits when:

1. The clinical assessment can be adequately performed via telemedicine (the investigator can obtain the necessary clinical information remotely)
2. Participant safety is not compromised by the remote format
3. The investigator has the qualifications and technology to conduct the assessment remotely
4. The telemedicine platform meets applicable privacy and security requirements (HIPAA, 21 CFR Part 11)

What Can and Cannot Be Done Via Telemedicine

Investigator Oversight

The PI remains responsible for the conduct of the trial regardless of the mode of participant interaction. For telemedicine visits, the PI must ensure:

• The telemedicine platform is appropriate for the clinical assessment
• The assessment is documented in the study records
• Any findings requiring in-person follow-up are identified and scheduled
• The telemedicine visit is conducted by a qualified individual (PI, sub-investigator, or appropriately delegated study staff)

Local Laboratories and Imaging

Using Local Labs

DCTs often use local (non-site) laboratories for participant convenience. FDA's guidance permits this approach, with the following considerations:

Home Phlebotomy

Mobile phlebotomy services can collect blood samples at participants' homes. Regulatory considerations:

• The phlebotomist must be qualified and licensed per state law
• Sample collection, handling, and transport must follow validated procedures
• Chain of custody documentation must be maintained
• The sponsor must ensure sample integrity during transport (temperature control, timing)

Local Imaging

Participants may undergo imaging at local radiology facilities rather than the trial site. The sponsor must ensure:

• Imaging protocols are standardized across facilities
• Equipment calibration and quality control meet study requirements
• Image reading is performed by qualified personnel (often centrally)
• Images are transmitted securely to the sponsor or central reader

Direct-to-Patient Drug Shipment

Regulatory Framework

FDA permits direct-to-patient (DTP) shipment of investigational products under certain conditions. The December 2023 draft guidance addresses DTP considerations:

Investigator Responsibility for DTP

Under 21 CFR 312.62(a), the investigator is responsible for the control of investigational drugs. In a DTP model:

• The PI must have oversight of drug dispensing, even if a pharmacy or logistics provider handles physical shipment
• The PI must be able to verify that the participant received the correct product
• The PI must have a process for drug accountability that does not rely on site-based inventory
• The PI must be able to halt drug shipment if safety concerns arise

Practical Challenges

Data Integrity in Remote Settings

21 CFR Part 11 Considerations

Electronic records and electronic signatures in DCTs must comply with 21 CFR Part 11:

Data Quality from Remote Sources

Source Data Verification

In traditional trials, monitors verify source data at the site. In DCTs, source data may originate from:

• EHRs at local healthcare facilities
• ePRO platforms
• Wearable device data platforms
• Telemedicine session records
• Local laboratory information systems
• Pharmacy dispensing records

The sponsor must ensure that monitors can access and verify source data regardless of where it originates. This may require:

• Data sharing agreements with local healthcare providers
• Direct access to ePRO and wearable data platforms
• Centralized data repositories that aggregate remote data sources
• Risk-based monitoring approaches that prioritize critical data points

Technology Platforms for DCTs

Platform Categories

Technology Validation

DCT technology platforms are subject to validation requirements:

• Computer system validation (CSV): Platforms used to collect, transmit, or store clinical trial data must be validated per 21 CFR Part 11 and GAMP 5 principles
• Device validation: Wearable devices and sensors used as clinical endpoints must be validated for accuracy, precision, and reliability in the intended use population
• Platform security: HIPAA compliance, encryption, access controls, penetration testing

IRB Considerations

IRB Review of DCT Elements

IRBs (Institutional Review Boards) review and approve DCT-specific elements:

Single IRB Requirement

Under the revised Common Rule (45 CFR 46.114) and the NIH single IRB policy, multi-site clinical trials conducted in the United States must use a single IRB (sIRB) for the portion of the trial conducted domestically. DCTs that span multiple states are subject to this requirement. The sIRB must have jurisdiction and expertise to review DCT-specific elements across all participating locations.

State-Specific Research Regulations

Some states have specific research regulations that affect DCTs:

Practical Guidance for Sponsors

When DCTs Are Appropriate

FDA Engagement

Sponsors should discuss DCT plans with FDA early in development:

IND/IDE Amendments

DCT elements must be described in the IND or IDE:

• Protocol: Detailed description of which trial activities will be conducted remotely, the technology platforms used, and the procedures for maintaining participant safety and data integrity
• Investigator's Brochure (if affected): Updated handling, storage, and administration instructions for DTP
• IND amendments: If DCT elements are added after the initial IND filing, submit a protocol amendment

Risk-Based Monitoring for DCTs

ICH E6(R2) promotes risk-based monitoring. In DCTs, the monitoring approach should account for:

• Centralized statistical monitoring of remote data sources
• Triggered site visits (or virtual visits) based on data quality signals
• Source data verification for critical data points through direct access to remote data platforms
• Technology platform performance monitoring (uptime, data transmission, device compliance)

Challenges and Limitations

Regulatory Uncertainty

As of early 2026, the December 2023 DCT guidance remains in draft. Until finalized, it represents FDA's current thinking but is not legally binding. Sponsors should follow the draft guidance but recognize that specific requirements may change upon finalization.

Geographic and Demographic Considerations

DCTs can improve trial access for geographically remote populations, but they may also introduce disparities:

• Digital divide: Participants without reliable internet, smartphones, or digital literacy may be excluded
• Language: DCT platforms may not support all languages needed for diverse enrollment
• Accessibility: eConsent and ePRO platforms must be accessible to participants with disabilities (ADA compliance)

International Considerations

DCT regulations vary by country. Key differences include:

Sponsors conducting global DCTs must harmonize across jurisdictions, which adds regulatory complexity.

Key Regulatory References

References