On July 27, 2023, the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) officially released and implemented the "Guiding Principles for Patient-Centered Drug Clinical Trial Design (Trial)" and "Guiding Principles for Patient-Centered Drug Clinical Trial Implementation (Trial)," along with the "Guiding Principles for Patient-Centered Drug Benefit-Risk Assessment (Trial)" (collectively known as the "Triple Release"). This comprehensive release covers the entire drug development lifecycle, offering systematic guidance for incorporating patient-centered approaches throughout clinical trials, encompassing design, implementation, and benefit-risk assessment. The "Triple Release" emphasizes the importance of integrating patient experiential data in clinical trials, optimizing patient participation experiences, and making scientifically sound decisions from patients' perspective.

Decentralized Clinical Trials (DCT) or Remote Intelligent Clinical Trials have emerged as innovative trial models in China, aligning with the concept of "patient-centered". The official implementation of the "Triple Release" has established principle-based requirements for various aspects of DCT, including remote patient recruitment, electronic/remote informed consent, remote visits, direct-to-patient drug delivery, patient experiential data collection, and remote monitoring, which will serve as a guiding framework for DCT practices in China. This article highlights the key changes between the draft for public comments and the trial version of the "Triple Release" and discusses the focal points of DCT in light of its content, aiming to provide valuable insights for industry professionals.

Internet Recruitment and Intelligent Recruitment

The "Guiding Principles for Patient-Centered Drug Clinical Trial Implementation (Trial)" (referred to as "Implementation Guidelines") have provided clear provisions for patient recruitment, suggesting the use of internet platforms and intelligent recruitment based on big data for patient information. Noteworthy revisions in the Implementation Guidelines regarding patient recruitment, compared to the draft for comments, include:

1. Internet recruitment platforms must employ language that is easy for patients to understand. Sponsors and researchers should ensure the platform accurately reflects the clinical trial's purpose and requirements.

    

2. Recruitment advertisements should be diverse to accommodate users' various reading preferences, while avoiding inflammatory or misleading content.

    

3. The mode of recruitment and information about potential subjects should receive approval from the ethics committee.

Additionally, the implementation of patient recruitment in DCT should consider the following aspects:

1. Internet recruitment platforms must take into account the needs of individuals who do not frequently use the internet to avoid potential selection bias in the recruitment population.

    

2. For intelligent recruitment based on big data for patient information, the sources and use of potential subject data should adhere to relevant laws and regulations. The scope of recruitment data and its sharing should be clarified in advance.

    

3. To ensure data security and prevent privacy breaches, the personal information of the person concerned shall be subject to a certain degree of de-identification.

In practice, patient recruitment for DCT may involve screening research institutions’ internal patient databases. However, certain questions require further clarification, such as whether it is necessary to obtaining informed consent from data subjects before screening, whether to utilize a self-built patient recruitment screening system within the research institution or employ a third-party system, and who should be responsible for de-identifying the data. In subsequent articles, we will delve into these issues based on our experience in DCT compliance management.

Electronic/Remote Informed Consent

The Implementation Guidelines propose the utilization of internet platforms and intelligent recruitment based on patient big data for patient recruitment. In comparison to the draft for comments, the Implementation Guidelines for electronic/remote informed consent encompass the following key aspects:

1. Ensuring that there is sufficient time for bidirectional communication between participants and physicians when using video explanations for electronic informed consent.

    

2. Allowing on-site staff to assist special populations (e.g., the elderly, children, or the physically challenged) in completing the electronic informed consent.

    

3. Ensuring that participants can contact physicians when they have questions about the informed consent form.

    

4. Providing general provisions for electronic signatures, adhering to national or international requirements.

    

5. Removing broad provisions related to  informed consent.

It is worth noting that while the Implementation Guidelines have removed provisions concerning "broad informed consent", its use is not necessarily nullified. Existing guidelines, such as the "Information Security Technology - Healthcare Data Security Guide", still contains provisions for broad informed consent that authorize identifiable data for future clinical research after de-identification. We anticipate the introduction of similar specific rules on the application of broad informed consent, such as 45 CFR 46.116(d), will be forthcoming to facilitate the development of DCT in China.

Additionally, other considerations for electronic/remote informed consent include:

1. Ensuring real-time communication with potential participants to facilitate their understanding in remote settings.

    

2. Ensuring the confidentiality of the informed consent process and information generated.

    

3. Ensuring that electronic or remote informed consent records are legally compliant and traceable.

    

4. The informed consent form should provide comprehensive information to potential participants about the use of new technologies, data collection scope, benefits, potential risks, accessibility, and time frames for accessing participant data.

In practice, it is essential to supplement traditional informed consent forms with the required information specified in the Implementation Guidelines, such as:

1. Explaining the benefits and risks that the DCT technology/platform may bring to participants in the clinical trial.

    

2. Describing the specific use of relevant DCT technology/platform (e.g., instructions for using an app or mini-program).

    

3. Specifying the types of data that will be collected, who will have access to the data, and the duration of accessibility.

    

4. In cases where the deployment of relevant app/mini-program servers involves cross-border data transmission, participants should be informed about the overseas recipients' names or organizations, contact information, processing purposes, methods, types of personal information, and procedures for exercising their rights with overseas recipients.

Remote Visit Data

Compared to the draft for public comments, the Implementation Guidelines have undergone several revisions regarding remote visits:

1. Specific scenarios of home visits and visits to medical institutions near the place of residence have been removed. Instead, the arrangement of remote visits should be based on potential safety risks to the subjects and the comprehensive consideration of the reliability of clinical data to ensure its rationality and feasibility.

    

2. The trial protocol must clearly explain the optional methods for conducting visits and the criteria for their selection.

    

3. Researchers are required to take measures to confirm the identity of the subjects during each visit.

    

4. The focus on accepting medical examination and test data from different medical institutions is clarified.

    

5. The requirement for researchers to authorize and train operating personnel has been removed. Now, sample testing laboratories and medical examination equipment involving medical judgment should have corresponding qualifications, ensuring that the adopted equipment and personnel have undergone relevant evaluations and qualifications recognition.

The trial version no longer lists specific remote visit scenarios but clarifies the factors to consider when arranging remote visits. Sponsors and researchers can now comprehensively consider and arrange remote visit methods in a way that reflect patient needs. This revision increases the flexibility and autonomy of remote visits, which helps to better meet individual patient needs and provides more space and possibilities for clinical trial innovation and optimization.

Additionally, the trial version has removed the requirement that researchers must "authorize and train" operators from medical institutions near the place of residence. This moderately relaxes the requirements for managing external personnel ("off-site personnel"). However, it is important to note that this does not mean that the oversight of off-site personnel can be completely ignored. Article 16(6) of GCP (Good Clinical Practice) stipulates that if researchers and clinical trial institutions authorize off-site personnel to undertake responsibilities and functions related to the clinical trial, complete procedures should be established. Therefore, if the use of medical institutions outside the research center for remote visits is considered, it is necessary to design a sound management process for off-site personnel in advance and to implement their supervision.

The Implementation Guidelines also require sponsors and/or researchers to conduct risk assessments of safety events in advance and to establish contingency plans in the trial protocol. This requirement aligns with the FDA's Decentralized Clinical Trials (DCT) Draft Guidance released on June 20, 2023, regarding the assessment and management of adverse events in remote visits. The contingency plan can be established considering the types and risk levels of safety events, the monitoring requirements for safety events by subjects, researchers, and sponsors, the handling requirements for safety events of different risk levels, and the requirements for recording safety events, among other content.

DTP（Direct-to-Patient）

Compared to the draft for public comments, the Implementation Guidelines provide illustrative examples of different situations where DTP (Direct-to-Patient) can be applicable:

1. For some orally administered drugs or drugs that can be self-administered at home, DTP can be considered.

    

2. Drugs with long shelf life and can be stored at room temperature may also be suitable for DTP.

    

3. For some drugs that require intravenous infusion or need to be administered by medical staff, DTP is generally not recommended.

In other words, DTP may be cautiously considered for most injectable biologics or drugs that require refrigeration, while orally administered drugs that can be stored at room temperature are more suitable for DTP.

The trial version also specifies that researchers and clinical trial institutions are responsible for directly delivering the investigational drug to the patient's side and, after the patient takes the drug, retrieving or disposing of the remaining medication according to the protocol. This requirement aligns with GCP, which states that drug management is the responsibility of the researchers/clinical trial institutions. If the researchers/clinical trial institutions delegate the drug dispensing and transportation to a third-party organization in DTP, they should grant authorization to the third-party organization.

In addition to the above changes, several key points need to be considered for DTP:

1. Researchers should ensure that each subject fully understands how to take and store the medication based on their individual circumstances.

    

2. Sponsors and/or researchers should develop a contingency plan for handling safety events, ensuring that subjects can receive appropriate medical care and be informed in advance.

    

3. Researchers are advised to conduct regular follow-ups with subjects and keep track of the returned drug quantity to ensure subject compliance with drug administration requirements.

    

4. A comprehensive quality control of the investigational drug should be established to ensure its quality during transportation and storage. For example, temperature control during transportation and ensuring that subjects are familiar with proper storage conditions and protocols for the drug at home.

In practice, establishing a full-process quality control of the investigational drug is crucial for ensuring the compliance of DTP operations. The quality control process can cover the trigger and confirmation of DTP orders, drug retrieval, drug dispensing, drug transportation, drug receipt, drug administration requirements, subject compliance follow-ups, drug returns, and more. Additionally, for drugs requiring temperature-controlled transportation, the quality control process should include real-time temperature monitoring, temperature exceeding alarms, and procedures for handling drugs that exceed temperature limits or become damaged.

Collection of Patient Experience Data

Compared to the draft for public comments, the Implementation Guidelines offer specific clarifications on the collection of Patient-Reported Outcomes (PRO) data:

1. Emphasis is placed on having qualified researchers transcribe and assess Clinical Outcome Assessment (COA) results without intervening in patient outcome reporting or making any modifications to the results.

    

2. When different collection methods are used (e.g., electronic and paper-based, remote and on-site), the consistency of measurement results should be evaluated.

    

3. The paper-based COA version can be converted to the electronic COA ("eCOA") version after assessment and validation by the sponsor for use in the clinical trial.

    

4. The collected eCOA data should meet the requirements of the paper-based COA and adhere to copyright and usage restrictions.

COA serves as a commonly used data collection tool in current DCT projects, and the trial version also considers the differences and requirements between paper-based and electronic versions for clinical trial applications. Sponsors are reminded to obtain relevant copyright and usage permits when employing eCOA.

Additionally, several key points must be considered for PRO data collection:

1. Attention should be given to de-identification and the protection of patients' personal privacy data during the collection process.

    

2. The frequency and duration of COA assessments should align with the natural course of the disease or symptoms, research objectives, and study duration.

    

3. The design of assessment time points and other processes should be reasonable, aiming to minimize the burden on subjects and reduce data missing through reminders and supplementary filling functions.

    

4. Compliance with regulatory requirements for recordkeeping, maintenance, and access must be ensured.

    

5. If digital medical technologies are used, the impact on data quality should be considered, and the traceability of data collected directly from the subjects should be ensured.

In practice, when eCOA is employed to collect patient experience data, sponsors and researchers should explore methods to ensure accurate and timely reporting of relevant data by subjects, maintain the authenticity and accuracy of eCOA data, and safeguard subjects' personal privacy. DCT projects can implement call centers to remind patients to accurately and promptly fill in eCOA data, while Clinical Research Associates (CRAs) can perform daily audits of eCOA data. Furthermore, the data entered by subjects in the electronic log should be unmodifiable after submission, and any data modification process should be strictly controlled and require multiple approvals.

Personal Data Protection and Security in Remote Monitoring

Monitoring is a crucial method for sponsors to ensure the quality of clinical trials. The Implementation Guidelines have undergone changes compared to the draft for public comments, as outlined below:

1. It explicitly states that sponsors have the option to use various monitoring methods, including Decentralized Clinical Trials (DCT), based on risk assessment, and the monitoring plan should also be risk-based.

    

2. Specific measures for encrypting or de-identifying source data in personal information protection and data security have been removed. Instead, sponsors are required to adopt measures to protect subjects' personal information and data security during remote monitoring, in accordance with relevant regulations such as the "Personal Information Protection Law."

The trial version aligns with the concept of "risk-based" in line with GCP principles under ICH-E6R3 draft for public comments and the NMPA's risk-based approach to registration inspection, providing sponsors with more operational flexibility while ensuring compliance with laws and regulations.

In addition to the above changes, other key considerations include:

1. Determining system access permissions and scope, such as accessing data of participating subjects only or read-only access.

    

2. The remote monitoring platform used should undergo validation and have a secure login process.

    

3. Remote monitors should receive appropriate training to conduct remote monitoring in a confidential and secure network environment, and to ensure that all monitoring records are adequately preserved.

In practice, protecting subjects' personal information during remote monitoring, ensuring the security of remote monitoring data, and setting up the remote monitoring system to access source documents are critical aspects. If discrepancies are found during remote monitoring, such as incomplete de-identification, doubtful authenticity, missing parts of the content, or inability to access certain files in the investigator's or subject's folders, sponsors need to make informed predictions and develop compliant solutions based on legal and regulatory requirements and project circumstances.