Vivek Vaishya

Documentation is instrumental in proving the creditability of clinical trials. The documents need to be complete and accurate in order to ensure compliance with ethics, GCP, and applicable regulations. A database used for documentation occupies the center stage of the clinical research.

 The emerging concepts of clinical research transformation, such as decentralized clinical trials, patient-centric clinical trials and community-based clinical trials, are rapidly gaining popularity.

 This scientific perspective will welcome another major change post the paper to electronic transformation, predominantly characterized by the direct involvement of participants instead of the classical sponsor-investigator approach. The clinical research will presumably be an activity of mass, rather than an activity led by the medical personnel. As a restructuring effort, any major pharmaceutical companies will require to adopt various secondary changes in the upcoming years. These changes will range from the inclusion of advance data capturing technologies, like the Internet of Things (IoT), to the management of operational documents in the clinical research.

The trial master file (TMF) is a repository of all essential documents related to the management and conduct of clinical trials right from their inception to the completion of archival period, and is critical to any clinical trial management, essentially for ensuring compliance with applicable regulations.

 In the era of electronic processing-led transformation, TMF has transformed data from paper documents to an electronically managed database. eTMF (electronic trial master file) can handle multiple stakeholders from different geographies in real-time.(Figure 1)

A lean and robust system for the management of clinical trial documents is required for maintaining the momentum of a clinical research. Moreover, stringent regulations demand clean, complete, and diligent documentation of the clinical trial data that is meant to be audit and inspection ready at all times. Auditors are required to tally the data across scanned documents and their digital copies for validating the legitimacy and correctness of the documents. Clinical trials consist of documents being updated at different geographical locations by different staff members for meeting regulatory requirements. With the advancement in clinical research, constant expansion in the scope of study, and the complexity of studies, document collection will prove to be a challenge while accessing documents during inspection and synchronization.

When clinical trials involve multiple stakeholders from different organizational sites and geographies, revising documents using diverse software and keeping track of rapid updates in documents are not possible with the current versioning systems used in eTMF. The lack of stepwise versioning in a document creates conflicting versions of the document, leading to the disarray of version control and document parity mismatch in eTMF.

Any lack of oversight affects record-keeping, thus, ensuing costly reiterations, inaccuracy, and even risks to safety of patients.

 Although eTMF promises a secure archival of clinical records, it also encompasses severe complexities of being a cumbersome process.

The eTMF lacks crucial mechanisms that would enable easy identification of revisions made to the content of a document.

 Moreover, it allows files to be downloaded on local computers, which may be susceptible to possible fraudulent activities with a limited scope to identify the origin of these data breaches.

Additionally, searchability in the dashboard of eTMF is unstandardized and not user-friendly. The board search function and the use of non-uniform naming conventions by multiple stakeholders make it difficult to perform a quick search and locate the required files.

Inaccuracies and missing data is unavoidable. The massive amount of source documents generated by various sources such as lab, sponsors, sites, vendors etc. tend to introduce scalability problems leading to unreliable access management, thereby leading to a considerable wastage of time and effort. Document storage should provide reliable ‘role-based’ access control and prevent unauthorized access or modification of the trial data. Document revisions should be made with consensus among all the stakeholders involved during the entire trial period.

A clinical trial involving researchers from sites across diverse locations requires data to be cleaned and checked for inaccuracies before synchronizing it with other site data. Missing any of the requirement should alert the data operator at the corresponding site itself. Continuous trial data, like sensor data, should be automatically captured during the auditing phase.

Dispersed clinical trials lack the element of trust and transparency because of the enormous amount of data being generated and the documents shared with sites. The clinical trial volumes are increasing at a rapid pace with a projected annual growth of 5.7% until 2028.

 This growth is expected to present extra challenges for data collection and data preservation.

 Keeping this in mind, it is foreseen that eTMF will not suffice the need of a database for the fair and robust documentation of clinical trials. However, there does exist a technology which can be a one-stop solution to all these requirements—Blockchain.

Blockchain is a transactional ledger of a growing list of records called blocks. The blocks are chronologically ordered and linked cryptographically to their previous blocks.

 Each block contains hash of the previous block, timestamp, and the transaction data. Addition or alteration of the chain requires consensus from majority of sharing parties called nodes. Like other databases, blockchain is basically governed within an organization by a committee. This committee oversees the blockchain governance rules placed within an organization and regulates the entire blockchain system.

 Some of the salient features of a blockchain system are

Decentralized—The participating nodes are dispersed at multiple locations and connected only through a networking protocol, and yet their collective computational power and storage define the entire blockchain.

Immutable—Requirement of a huge computation power makes it practically impossible to alter blocks once they are added to the blockchain

Version control—Version control of all essential documents and any transactional activity is easily managed and disseminated in real-time. This activity is visible to all stakeholders. 

Access control—Blockchain provides different levels of access control to ensure that sensitive data is not accessed or modified by an unauthorized user.

Transparency—The documents evolve in the blockchain i.e., they are created, processed, and finally archived in the tool itself. This assures trust and transparency amongst various stakeholders pertaining to the data shared on blockchain.

Collaboration—Organizations can easily collaborate with one another through gossip protocol (a tool in blockchain that enables communication with stakeholders through computers).

Public blockchains, private blockchains, consortium blockchains and hybrid blockchains are the four basic forms of a blockchain network. Each of these platforms has its own set of advantages, disadvantages and ideal applications. The implementation team chooses the blockchain type depending on a variety of factors such as process requirements, size, usage and user base. Blockchain is the foundation that can be leveraged using platforms like Ethereum, Hyperledger Fabric, R3 Corda etc. In addition, blockchain has two kinds of licenses i.e., open-source and proprietary. While in the proprietary license, case procurement depends entirely on the service provider, the open-source licensed blockchain doesn’t require procuring. A few eTMF vendors do support blockchain but as far as the established vendors are concerned it is still a long-drawn process for them to move eTMF to a blockchain based solution.

Thus, this technology embraces vital features of healthcare and allied industries for successful documentation that involves multiple stakeholders where documentation is a crucial entity.

How will blockchain help in the digitization of eTMF?

Use of a blockchain network allows distributed storage of the eTMF data on blockchain in a more reliable and secured manner. The chronological ordering in blockchain largely prevents a 

 Blockchain infuses confidence among stakeholders for genuineness and sanctity of the entire clinical trial data stored in an eTMF-blockchain flow.

 It prevents analytical remodeling of the document and ensures document traceability to provide a robust and non-hackable automation tool with shareable parameters.

Blockchain technology enables the following features to enhance the eTMF functionality:

Secure and restricted access—Access management becomes highly secure with different levels of restrictions on users. Furthermore, automation via chain codes help in identifying the flow of data and ensuring that the stakeholders adhere to GCP (good clinical practice) guidelines.

Decentralized network—The decentralization feature of the tool enables a sturdy network to ensure that the stakeholders are well-connected. For e.g., if there is a failure at one node, the data can be fetched instantly from other nodes with maximum guaranteed uptime.

Trust and non-repudiation—Since blockchain ensures the controlled access and security of data, pharmaceutical companies would have a higher level of trust on it. The use of blockchain will ensure that the pharmaceutical companies, investigators, patients, Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and regulatory bodies have absolute confidence in the data, and that the informed consent is thorough, accurate and complete.

Version management—By managing the versions of documents on the blockchain, compliance to guidelines and regulations is ensured, and a standard is established. Each user/organization will view exactly the same data at any given point of time without any conflict unlike the traditional process of eTMF.(

 Users/organizations can even view the version history for auditing purposes.

Figure 4 eTMF using Permissioned Blockchain

The eTMF-blockchain technology offers a myriad of application benefits. These benefits predominately cater to the enhancement of efficiencies in terms of data quality and integrity while ensuring compliance to ethical standards. This will allow continuous sharing of clinical data between trial entities making it more reliable, credible, and transparent.

 This will also pave the way toward exploring a myriad of new application-based, future-proof solutions, such as:

Bifurcating channels for public and private data sharing.

Adding options for the provision of consensual access to regulatory bodies.

Eradicating paper as well as traditional eTMF systems by replacing them with e-forms.

Creating artificial intelligence- enabled tools to investigate data correctness and the execution of clinical trials.

is the Head of Life Sciences ADD Research & Innovation, and ADD A&I;

is a Developer; all of TCS ADD Platforms. 

is the Former Head of Research and Innovation for TCS ADD Platforms. 

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eTMF-blockchain technology offers a myriad of application benefits to data quality and integrity while ensuring compliance to ethical standards. 

Vivek Vaishya

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Future of Clinical Trial Documentation Management: eTMF Integrated with Blockchain