Blockchain - A Hyperledger Framework for Clinical Trials

t is fundamental to have a unique blockchain design for specific industry use cases such as finance, insurance, supply chain and healthcare. The majority of biomedical and healthcare applications require stakeholders as participants most likely to accept blockchain frameworks developed on private networks. Like cryptocurrencies for participation, they don't need impetus. Some are popular private blockchain achievements in Hyperledger, Ethereum.

Applications on private blockchains are ideal for secure data collection, management and sharing within healthcare organizations. In the case, based on the Ethereum platform, a private blockchain framework built MedRec, using this blockchain network to share electronic medical records between patients and healthcare providers.

Medical applications can use private blockchains to securely collect, manage and share data. For example, MedRec, a decentralized data management system based on Ethereum's private network, allows electronic medical records to be shared between patients and healthcare providers. The author used Ethereum for secure analysis and management of medical sensors. Built on Hyperledger Fabric, the Orange Consent Management System provides a consent management system for users to share health data. In this article, the authors used Hyperledger Fabric to develop a decentralized framework for consent management and secondary use of research data. The article also showed how smart contracts can be leveraged to enforce IRB regulation.

hyper ledger

The Linux Foundation has developed the Hyperledger Fabric framework. It is a private blockchain network that offers a modular architecture by supporting pluggable components such as consensus protocols, cryptography, identity management and membership services. A private network consists of multiple nodes, chaincode (business logic), and a ledger containing a state database and a log of transactions. Nodes can be managed by individual users or by multiple users. Based on Hyperledger's capabilities, nodes can be classified as clients (invoking transactions), peers (maintaining and updating the ledger), and orderers (supporting communication and maintaining transaction order).

Client node : Connected to both peer and orderer nodes. Send transaction calls to endorsers and transaction proposals to orderers.

Peer nodes : Their role is to commit transactions and maintain the state of the ledger world. Update the ledger after receiving the order status from the orderer.

Orderer Node: Creates broadcast communication services to guarantee delivery. After validating the acknowledgment message, it delivers the transaction to peer nodes.

A smart contract, also called chaincode in Hyperledger Fabric, is self-executing logic that represents an agreement or set of rules that govern transactions within a blockchain network. Rules are implemented as functions of the chaincode. Every data transaction that requires access to the ledger calls the corresponding chaincode function. Hyperledger Fabric implements approved policies or conditions to validate proposed transactions. When a transaction is proposed by a client, it must be approved by a predefined approval node. Suggested signatures are collected and sent to the orderer. The orderer verifies approval messages from all approvers, including valid number of approver signatures and simulated transaction results. Collected transactions are sent to all peers as new blocks. A trusted Membership Service Provider (MSP) registers network participants. MSPs provide verifiable digital identities to all entities within the blockchain network, including peers, orderers, and clients. It acts as a trusted authority that abstracts the process of issuing cryptographic certificates and user authentication. Other notable features of Hyperledger Fabric include:

Confidentiality: In addition to private networks, you can create private channels consisting of subgroups of network participants. All information related to a channel can only be accessed by members of that channel, increasing the level of confidentiality.

Encrypted Identity Management: The Membership Identity Service manages user identities and authenticates all participants on the network. Additional access controls can be implemented for specific network operations.

Modular Design: Supports a modular architecture that makes various components such as membership functions and consensus plug-and-play.

Blockchain network setup

It is important in blockchain to identify stakeholders or participants and their roles before starting to set up the network. For multi-site clinical trial protocols, the most important part of conducting a multi-site clinical trial is to recruit the following personnel:

Subjects— Individuals whose data are collected by investigators to conduct research studies. Data can be collected through intervention or interaction with each

Investigator Investigator (PI) — Investigator — The primary individual responsible for study preparation, conduct, and administration at each site in a multicenter clinical trial. while maintaining ethical conduct and research oversight. Protect the rights, safety and welfare of subjects enrolled in trials. Access data and specimens collected from subjects, analytical results, adverse event cases, and study reports.

Coordinating Center (CC) — The center responsible for coordinating multisite clinical trials. Produce data compilation reports, subject activity schedules and communicate to appropriate stakeholders. Maintain a central database that also stores SAS data.

Data Security Monitoring Board (DSMB ) — an independent expert who regularly reviews and evaluates accumulated study data on participant safety and study progress, and makes recommendations for continuation, modification, or termination of the study group.

Institutional Review Board (IRB) — A board designated to protect the rights, safety, and health of subjects participating in clinical trials. They review all aspects of the trial, including approval of test materials before and during the trial. A new NIH policy requires a single IRB (sIRB) to conduct ethical reviews of multisite studies.

Regulatory bodies— Regulatory bodies, such as the Food and Drug Administration (FDA), ensure that the medical treatments used by subjects are safe and effective. Conduct research site inspections to protect subject rights and verify data quality and integrity.

Sponsor —A person, institution, or organization that initiates, manages, or funds a clinical trial, but does not actually conduct it.

Analyst — A researcher or statistician who collects, reviews, and organizes trial results, including unidentified data collected from subjects.

We consider each person involved in a multi-site clinical trial to be a node in the blockchain network. A node can represent an individual (PI), an institution (covered institution), or an organization (sIRB). In a standard blockchain network, each node maintains a single ledger and works with smart contracts. The smart contract will enforce pre-approved research protocol guidelines, including how trial data will be collected, stored and shared. Raw data can be stored directly in the ledger. However, for large-scale data such as wearable sensor readings or genomic data, we recommend storing them off-chain using encrypted keys linked to the ledger.

Create a private channel

Hyperledger Fabric provides an additional level of data privacy by incorporating private channels between subsets of members within the network. The network will support multiple channels, each maintaining separate smart contracts and ledgers. Ensure confidentiality by making all data, including transaction, ledger, member, and channel information, invisible and inaccessible to members who are not explicitly authorized to access that channel. These lightweight channels further reduce the storage space and energy consumption required to maintain the blockchain network. Multiple channels improve transaction throughput by allowing transactions to run in parallel. Multi-site clinical trials incorporate private channels to streamline data flow and restrict data access to designated personnel. Divide your network into the following private channels:

Subject Enrollment Channel: Once a subject is determined to be eligible to participate in a clinical trial, the PI collects data, including consent and Protected Health Information (PHI), for enrollment. This channel supports consent management systems for clinical trials. Create private channels to manage registration-specific information so that only intended members of the blockchain network have access to such sensitive data. This includes PIs, Subjects, Coordination Centers, and DSMBs.

Trial Monitoring Channel: Raw data or samples are collected periodically by a trial site or clinic once a subject agrees to participate in the study. Create separate channels including PIs, DSMBs, Sponsors, Coordination Centers and Regulators to monitor the activity done in the trial. Members of this channel have access to study data collected from subjects, activities performed at each visit, study results, and cases of adverse events experienced during the study.

Data Analysis Channel: Analysts conduct analysis of unidentified data to gain insight into research effectiveness. Create data analysis channels between PIs and analysts to enable secondary sharing of anonymized data for analysis.

A blockchain-based system with private channels to manage data in multi-site clinical trials. Each participant maintains a ledger and operates on the smart contracts of its member channels. Further restrict unauthorized data access by maintaining information confidentiality, limiting access to channels, and restricting data transactions to channel members.

Research Report Channel: A clinical research report is a detailed document describing the methods and results of a trial. Integrate clinical and statistical descriptions, presentations and analyze results. Private channels consisting of PIs, sponsors, regulators, coordinating centers and subjects help manage and share research reports.

Therefore, in this framework each node maintains a ledger corresponding to each member channel, rather than a single ledger containing the entire trial data. Transactions within each channel are further governed by their own smart contracts. The proposed system design is based on an NIH-funded multisite clinical trial protocol, but can be extended to meet the specific requirements of other studies.

Implementing channel-specific smart contracts

Smart contracts are essential for implementing and enforcing clinical trial protocol4 guidelines. These programs can define a list of features that incorporate specific requirements for conducting clinical trials. Blockchain participants can interact with the application interface to invoke smart contract functionality. For each data transaction request, the corresponding function verifies whether a valid user has proposed for a valid channel, data type, and time. This allows fine-grained access control. Here we provide a detailed description of the smart contract specific to the above private channel.

Smart Contracts for Subject Enrollment: Each clinical trial protocol defines a set of inclusion and exclusion criteria that determine if a candidate is eligible to participate in the study. This often requires ascertaining the candidate's age, gender, prerequisites, and past treatments. A registration function within the smart contract can check a set of constraints before registering a candidate and adding data to the ledger. PIs are responsible for data anonymization, so they can trigger smart contract functions that disassociate clinical information from subject identifiable information. During enrollment, all sensitive information collected from subjects, including PHI and consent information, can be stored in a ledger. A smart contract can additionally check if a target member is trying to invoke a particular function. For example, subjects can attempt to read data stored by PI on the ledger. Similarly, DSMB members can have read or write access to this ledger. Restricting access to such sensitive information to designated members within your network further increases data privacy. Once approved, the subject's record is added to the ledger.

Trial Monitoring Smart Contract: The trial monitoring channel collects and manages various types of data during the trial. In a multisite research study, each clinic will conduct a predetermined set of activities based on a protocol-defined schedule of activities. This includes collecting questionnaires or samples from subjects, conducting laboratory tests, and reporting adverse events. This channel-specific smart contract can check whether the data corresponding to the scheduled activity was entered into the system during the approved timeline. In addition, you can check whether certain prerequisites have been met before data entry. Timely reporting of cases of adverse events and laboratory abnormalities is often difficult for current clinical trial management systems, so smart contracts can be leveraged to record, track and update these events in real time. . In addition to rapid intervention, it provides regulators with a transparent and reliable approach to event monitoring. Additionally, smart contracts will flag transactions and record them in an immutable transaction log if any discrepancies or attempts to tamper with the recorded data are made. In multisite trials, this framework ensures the provenance and quality of data collected from different sites. Implementing a single smart contract across all sites further ensures compliance with IRB-approved research protocols and a consistent data framework.

Smart Contract for Data Analysis: Anonymized data collected from subjects is shared with analysts for secondary data analysis. Combining the consent management system described above with smart contracts limits unauthorized data access, even with the most restrictive blanket consent. The smart contract checks the consent information stored in the ledger to confirm the validity of the request. Once approved, anonymized data in SAS format will be shared. Secondary research includes topics such as longitudinal data analysis, subgroup analysis, nonlinear relationships, and meta-analysis. Based on the underlying programming language, smart contracts can further call modules or functions that automatically run analytical code.

Research Report Smart Contract: A clinical research report is an integrated report containing clinical and statistical descriptions, presentations and analyses. It also includes sample case report forms, information related to research products, technical statistical documents, patient data listings, and technical statistical details28 such as derivations, calculations, analyses, and computer outputs. Smart contracts designed for this channel access transaction logs to automatically generate audits to assess participating sites' performance, protocol adherence, and trial effectiveness. This can significantly reduce the manual audit burden and incidents of selective, underreporting, or misreporting. This also applies to the regular generation of reports for ongoing review. This will improve the credibility and integrity of research reports submitted to regulatory authorities.

Protocol amendments are frequent in clinical trials, with an average of 2.3 amendments per trial. Where corrections are unavoidable, it is important to implement and track them across all participating sites and stakeholders. Implementing such amendments into the framework requires updating the channel-specific smart contracts so that all intended stakeholders are aware of and comply with the updates. This is achieved through a special high-level system chaincode that incorporates and tracks updates made to the channel-specific chaincode. To ensure transparency, design and validate authorization policies before initiating smart contract updates.

evaluation

We evaluate the effectiveness of the proposed data management system in conducting the key requirements of an NIH-funded multicenter clinical trial.
Audit trail: As pointed out in the Guide to Conducting High Quality Research in the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN), proper documentation of how research procedures are conducted is always required . Maintaining an audit trail includes regular monitoring of survey sites, review of survey compliance, and reports on visit monitoring. Current systems rely on manual processes to record and maintain documentation, resulting in staff turnover or unplanned emergencies. Blockchain keeps an immutable log of data transactions and recorded activity, eliminating the need for paper trails. Attempts to tamper with encrypted and secure transactions are automatically flagged and reported. This stringent standard for research supervision improves the traceability and fidelity of research.

Data Privacy: Unlike traditional systems, private blockchain frameworks with private channels offer a high degree of data privacy. As discussed earlier, blockchain and smart contracts enable secure consent management and secondary data sharing. PIs can use the system to anonymize data, store sensitive information in ledgers, and store anonymized data in databases using encrypted keys. Based on consent information stored in the ledger, third-party researchers access data anonymized using one-time encryption keys. This restricts access to data if permissions are revoked. Smart contracts further restrict unauthorized data use with fine-grained access control. Individuals can be granted data access permissions for specific data types and time periods. Private channels enhance data privacy without affecting transaction efficiency. A recent study showed how a multi-channel setup can improve transaction throughput by allowing multiple independent transactions to run in parallel.

Data Integrity: The provenance and integrity of data ensures the validity of research and its results. Data collection and reporting must follow approved guidelines and standardized representations. This is particularly relevant for multisite studies, where raw data, questionnaires, and lab reports are collected and managed by multiple participating sites and their personnel. Distributed systems like blockchain facilitate data entry. It is time-stamped and nearly impossible to fake if it exists on your system. This automatically strengthens system trust without a central authority of trust. To enforce data integrity and consistency across all sites, smart contract functionality defines and validates a set of criteria that must be met prior to data entry. Prior to data entry, you can verify that eligibility criteria such as inclusion and exclusion criteria have been met, the site follows a schedule of activities for each visit, and data standards such as HL7 and SNOMED CT. This reduces cases of data fraud or inconsistencies that are typically detected later in the trial.

Protocol Violations: Protocol violations reduce benefits, increase risks, and impact subject safety and welfare, and data integrity. Once a clinical trial protocol is approved using current clinical trial management systems, it is difficult to ensure compliance by all sites and personnel. A smart contract can verify whether certain constraints required by the protocol are met. This includes, but is not limited to, insufficient informed consent, patient enrollment criteria, misreporting or underreporting of events, etc. With constraint checking and automatic monitoring, smart contract functionality detects and records cases of protocol violations. In addition, it assists in the automatic generation of reports to notify regulatory bodies such as DSMB and IRB of such incidents. Accurate and timely reporting of protocol violations is essential for interpreting results and designing post-approval safety assessments for new interventions.

Protocol Amendments: Amendments to clinical trial protocols can be challenging for data analysis and interpretation, especially if they occur mid-study and may introduce bias if the changes are made on the basis of trial data. there is. Implementing and communicating amendments is also burdensome and can be costly. Once the protocol is amended, all sites must adopt and adhere to the updated guidelines. Smart contracts implementing protocol guidelines are updated upon approval from appropriate members and installed on all nodes to enforce updated guidelines and ensure consistency. All other channels can continue to work with their existing versions if the fix requires channel-specific smart contract updates. So the framework not only provides a transparent approach to version control, but also a modular design for implementing modifications.

Adverse Event Reporting: In order to meet its obligations during the conduct of clinical research, IRBs must have information about unanticipated issues, including risks to human subjects in the study, including adverse events that are considered unanticipated issues. it won't work. Failure to or delay in reporting adverse events can have a serious impact on subject safety and welfare, study outcomes, and study efficacy. Adverse event reporting is a multi-step process and is often delayed due to manual intervention and lack of a sophisticated approach to reporting. Smart contract functionality triggered by study coordinators, PIs, or affected subjects enables real-time, automated reporting of adverse events to facilitate intervention. These features can also check if follow-up studies for assessment have been completed. Access transaction logs to easily track and monitor harmful events. Such an approach enables timely identification of adverse events and addressing patient safety.