On May 28, 2024, the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA)  issued the Technical Guiding Principles for Applying Decentralized Clinical Trials in Rare Disease Drug Clinical Development (hereafter referred to as the Rare Disease DCT Guiding Principles or the Guiding Principles). These principles offer guidance on how to conduct DCTs scientifically and in accordance with standards in the context of rare disease drug clinical development. The Rare Disease DCT Guiding Principles comprehensively incorporate key concepts from ICH E6(R3), such as risk-based quality management (RBQM), patient-centricity, and data authenticity, reliability, and traceability. The industry has increasingly recognized that DCT compliance should be rooted in systematic risk assessment, aligning with the RBQM approach. This involves promoting the implementation of Good Clinical Practice (GCP) process redesign in research institutions, strengthening vendor compliance management, and providing compliance training for clinical trial staff, thereby embodying the principles of patient-centricity and data authenticity, reliability, and traceability. Furthermore, establishing a compliance evidence chain for DCT implementation ensures data authenticity, completeness, and traceability. These measures contribute to maximizing the protection of subjects' rights and interests while enhancing the overall quality of clinical trials. This article draws upon project experience to analyze the main content of the Guiding Principles and offer recommendations for applying DCT in drug clinical development.

I. DCT Compliance Risk Assessment: The Foundation of “Risk-Based Quality Management”

The Rare Disease DCT Guiding Principles strongly emphasize the importance of conducting thorough compliance risk assessments as the foundation for implementing RBQM in decentralized clinical trials (DCTs). These risk assessments are crucial for identifying and mitigating potential issues that may arise due to the unique challenges and complexities associated with DCTs.

(I) How the Rare Disease DCT Guiding Principles Address RBQM

The Guiding Principles provide a comprehensive framework for addressing RBQM in the context of rare disease DCTs. Chapter 3 of the guidelines focuses specifically on the potential risks associated with the use of digital health technologies (DHTs) in DCTs and recommends conducting benefit-risk assessments of proposed DCT elements during the planning stage.

The guidelines stress the importance of establishing a robust quality management system before the trial begins and developing proactive countermeasures for known or potential risks. Sponsors are advised to thoroughly identify changes in key quality elements that may occur in the DCT model and DHT application process and perform benefit-risk assessments and risk management accordingly.

Chapter 6 of the guidelines provides detailed guidance on developing an effective risk control plan. It stipulates that sponsors should conduct comprehensive risk assessments, identify potential risks related to data quality, privacy, and security, and develop contingency plans to minimize the impact on patient safety when planning to implement DCT.

Moreover, the guidelines emphasize the critical role of training and education as primary measures for risk control in DCT projects. Chapters 4 and 5 particularly highlight the need for "providing adequate training" when discussing the design and implementation of DCT for rare disease drugs and the use of nearby medical resources, respectively.

By following the Guiding Principles and conducting thorough compliance risk assessments, sponsors and researchers can lay a solid foundation for implementing effective RBQM strategies in rare disease DCTs. This proactive approach to risk management helps ensure the quality, integrity, and reliability of clinical trial data while safeguarding trial participants’ rights, safety, and well-being of.

(II) Implementing Compliance Risk Assessment and Training

Sponsors and researchers should focus on the compliance risks of DCT elements, systems, research institution processes, vendor qualifications, and the protection of subjects' rights and interests. A DCT implementation plan should be formulated to explore potential hidden risks. Based on the risk assessment results, targeted prevention and response measures should be developed, focusing on medium and high-risk points to minimize the possibility and impact of risks.

Sponsors should conduct training for various participants in clinical trials, especially researchers, CRCs, and vendors, to help ensure the quality of clinical trials. The training can include the overall DCT design and implementation process, DHT and equipment/software, data security and personal information protection, and safety monitoring.

II. Reengineering GCP Compliance Processes in Research Institutions to Implement the "Patient-Centricity" Concept

The Rare Disease DCT Guiding Principles recognize the need for research institutions to adapt and reengineer their GCP compliance processes to effectively implement the "patient-centricity" concept in decentralized clinical trials (DCTs). This involves a comprehensive review and optimization of existing processes, policies, and procedures to ensure that trial participants’ rights, interests, safety, and well-being remain the top priority throughout the DCT process.

Reengineering GCP compliance processes in research institutions is essential to address the unique challenges and opportunities presented by DCTs. This may include adapting informed consent procedures, data collection methods, and safety monitoring practices to accommodate remote or virtual trial participation. Research institutions must also consider the implications of involving third-party vendors and local healthcare providers in the DCT process and establish clear lines of communication, oversight, and accountability.

(I) How the Rare Disease DCT Guiding Principles Address "Patient-Centricity"

The Rare Disease DCT Guiding Principles place a strong emphasis on the concept of "patient-centricity" and provide specific guidance on how research institutions can incorporate this principle into their GCP compliance processes. The guidelines recognize that DCTs adopt new methods and models that involve the protection of subjects' personal privacy, data security, and other compliance issues, requiring special consideration when designing and implementing GCP compliance processes.

The Guiding Principles stress that the rights, interests, safety, and health of subjects should always be the top priority when designing and implementing DCTs. This patient-centric approach is reflected in various aspects of the guidelines, such as:

• Emphasizing the importance of fully informing subjects about the scope of data collection and access rights during the electronic informed consent process and protecting their privacy.

• Clearly defining the specific responsibilities of sponsors, researchers, and other parties involved in the DCT process to ensure proper oversight and protection of trial participants.

• Recommending that researchers properly supervise personnel or related parties carrying out authorized activities to ensure the rights, interests, safety, and health of trial participants, as well as the reliability of data.

By following the Guiding Principles and reengineering their GCP compliance processes accordingly, research institutions can ensure that the "patient-centricity" concept remains at the forefront of their DCT activities. This approach not only helps protect the rights and well-being of trial subjects but also enhances the overall quality, integrity, and reliability of the clinical trial data generated through DCTs.

(II) The Necessity for Research Institutions to Implement GCP Compliance Process Reengineering

According to GCP regulations, clinical trial institutions and researchers are responsible for implementing informed consent, visits, paying subject compensation, managing investigational drugs, etc. In DCT projects, research institutions and researchers will authorize DCT vendors to undertake some of these responsibilities. To manage DCT vendors throughout the process, ensure the quality of trial procedures outside the research institution, and obtain scientific, true, and reliable data and results, research institutions need to implement GCP compliance process reengineering.

This involves optimizing and updating management norms and operation processes to ensure compliance with GCP, the Rare Disease DCT Guiding Principles, and relevant laws and regulations. For example, the "centralized pharmacy management model" is often adopted in traditional projects. In DCT projects, the "DTP/STP" model may be involved, requiring process reengineering for matters such as authorization of drug distribution entities, overtemperature or damage to drugs during transportation, randomization, and logistics of drug distribution, and disclosure of subjects' personal privacy.

The principles of "patient-centricity" and "fitness for purpose" require research institutions to collect and listen to patients' voices before implementing DCT, understand the difficulties and pain points of specific patient populations, and implement DCT to solve these issues. Such information can be used as one of the key quality elements of clinical trials and incorporated into the full-cycle management of rare disease DCT trials. Failing to implement GCP compliance process reengineering can lead to various consequences, such as affecting EC reporting, information system access, clinical trial implementation, future registration review, and regulatory inspections, and causing project delays or obstacles.

III. Vendor Compliance Management and Compliance Evidence Chain Construction to Ensure Data Authenticity, Reliability, and Traceability

In decentralized clinical trials (DCTs), the involvement of third-party vendors and the use of digital health technologies (DHTs) introduce new challenges and complexities in ensuring data authenticity, reliability, and traceability. To address these challenges, the Rare Disease DCT Guiding Principles emphasize the importance of implementing robust vendor compliance management and constructing a comprehensive compliance evidence chain.

Vendor compliance management refers to a systematic approach to assessing, monitoring, and managing the compliance of third-party vendors involved in the DCT process, which includes evaluating vendors' qualifications, experience, and adherence to relevant regulations and guidelines, as well as establishing clear expectations and performance metrics. Effective vendor compliance management helps ensure that vendors meet the necessary standards for data integrity, security, and privacy, and that their activities are properly integrated into the overall DCT process.

Constructing a compliance evidence chain involves documenting and maintaining a complete and auditable record of all activities, decisions, and data flows throughout the DCT process. This evidence chain should cover various aspects of the trial, including protocol design, subject recruitment, informed consent, data collection, transmission, storage, investigational drug management, and safety monitoring. By establishing a robust compliance evidence chain, sponsors and researchers can demonstrate the authenticity, reliability, and traceability of clinical trial data and ensure that the trial is conducted in accordance with applicable regulations and guidelines.

(I) How the Rare Disease DCT Guiding Principles Address Vendor Compliance Management and Data Traceability

The Rare Disease DCT Guiding Principles provide specific guidance on how sponsors and researchers can address vendor compliance management and data traceability in the context of rare disease DCTs.

Regarding vendor compliance management, the guidelines recommend that sponsors and researchers:

• Conduct thorough due diligence on potential vendors to assess their qualifications, experience, and compliance with relevant regulations and guidelines.

• Establish clear expectations and performance metrics for vendors and continuously monitor and evaluate their performance throughout the DCT process.

• Provide necessary training and support to ensure that vendors understand and adhere to the specific requirements of the DCT protocol and relevant regulations.

In terms of data traceability, the guiding principles emphasize that:

• The source data and files of the DCT system should be able to be used to fully reconstruct and evaluate the clinical trial-related processes, reflecting the protection of subjects, protocol execution, data recording, result reporting, etc., and be available for review when needed.

• All relevant parties (including DCT vendors) should understand and perform their responsibilities and ensure compliance with relevant laws and regulations.

• Research institutions and researchers should authorize relevant vendors as necessary according to clinical trial needs and properly supervise personnel or related parties who perform authorized activities to ensure the rights and interests, safety and health of trial participants, and the reliability of data.

By following the Guiding Principles and implementing effective vendor compliance management and compliance evidence chain construction, sponsors and researchers can ensure the authenticity, reliability, and traceability of clinical trial data in rare disease DCTs. This approach helps maintain the integrity of the clinical trial process, protect the rights and well-being of trial participants, and support the development of safe and effective treatments for rare diseases.

(II) Implementing Vendor Compliance Management in DCT Projects as Foundation for Data Compliance

DCT vendor compliance management should focus on ensuring the authenticity, reliability, and traceability of data in the DCT process. It is recommended to carry out vendor compliance management from the following aspects:

• Strengthening training and assessment of GCP-related knowledge

• Establishment and verification of vendor compliance system

• Assessing vendors and establishing a whitelist system

(III) Constructing a Compliance Evidence Chain to Ensure Data Authenticity, Reliability, and Traceability

While conducting vendor compliance management, a complete compliance evidence chain should be constructed throughout the implementation process of DCT projects, covering various links such as protocol design, subject recruitment, informed consent, data collection, transmission and storage, investigational drug management, and safety monitoring. The key points of constructing a compliance evidence chain include:

• Forming complete trial protocol design and ethical review documents

• Ensuring subject recruitment and informed consent process comply with ethical principles and are fully traceable

• Establishing data management plans, clarifying data standards, coding specifications, verification, and proofreading processes, etc., for data collection, transmission, and storage

• Adhering to protocol requirements for investigational drug distribution and recovery, with drug temperature monitoring, transportation verification, and retention of handover documents

• Conducting timely, accurate, and complete safety monitoring and serious adverse event reporting

In summary, organically combining vendor compliance management and compliance evidence chain construction to form a full-chain and full-process quality management is essential to ensure data authenticity, reliability, and traceability during the implementation of DCT projects. This requires the joint efforts and practices of all relevant parties, including sponsors, researchers, and vendors.